Detoxification and Cleansing Programs

Detoxification and Weight Loss

Detoxification and Weight Loss

Detoxification is something that is very important to the body, but it is something that isn't understood well. Centuries ago, health masters in the East understood the importance of balancing and detoxifying the body. It's something that Western medicine is only beginning to understand.

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Inherited Peripheral Neuropathies

Reactive Microglia

FIGURE 1.19 The glutamate-glutamine cycle is an example of a complex mechanism that involves an active coupling of neurotransmitter metabolism between neurons and astrocytes. The systems of exchange of glutamine, glutamate, GABA, and ammonia between neurons and astrocytes are highly integrated. The postulated detoxification of ammonia and inactivation of glutamate and GABA by astrocytes are consistent with the exclusive localization of glutamine synthetase in the astroglial compartment. Gln, glutamine. FIGURE 1.19 The glutamate-glutamine cycle is an example of a complex mechanism that involves an active coupling of neurotransmitter metabolism between neurons and astrocytes. The systems of exchange of glutamine, glutamate, GABA, and ammonia between neurons and astrocytes are highly integrated. The postulated detoxification of ammonia and inactivation of glutamate and GABA by astrocytes are consistent with the exclusive localization of glutamine synthetase in the astroglial compartment....

Complications of Migraine

Patients with acute status migrainosus may require hospitalization, particularly if the condition was induced by dependency on medication, is accompanied by dehydration, or if the patient is depressed or has a prior experience of adverse reactions to medications (Table I). The offending medication causing rebound headache phenomenon must be withdrawn. The withdrawal is usually done in an abrupt manner, but all precautions to prevent seizures and or other withdrawal reactions should be instituted. Treatment for patients with status migrainosus should be aggressive and includes rest rehydration and electrolyte replacement detoxification round-the-clock parenteral analgesic therapy symptomatic treatment of nausea, anxiety, insomnia, and withdrawal symptoms concurrent initiation of prophylactic therapy and behavioral treatment. Corticosteroids and NSAIDs are

Metabolism and Excretion of Toxicants

Metabolism Nsaids Liver

Thus, the liver is the richest source of enzymes for metabolizing toxicants, but there is ample evidence that enzyme systems are ubiquitous, which can be rationalized on the basis of the importance of such enzymes in detoxifying various compounds. Intestinal microflora plays an important role in the biotransformation of One of the unique facets of toxicant metabolism is that even though structures of these potentially toxic products, be they natural or synthetic, are so tremendously varied, the body seems to have evolved detoxifying processes that can cope with almost any of the many different compounds. Animals possess enzymes that can metabolize drugs, pesticides, secondary plant metabolites, and synthetic compounds as defense mechanisms, which are likely because of evolution in response to selective pressures for protection against many naturally occurring toxic products. There are two categories of animal enzyme systems (1) those for the transformation of normal endogenous...

Patient preference and compliance

Glycoprotein Gut Wall

P-glycoprotein (PGP, ABCB1) is a member of the family of ATP-binding cassette drug transporters that is abundantly expressed in the intestinal mucosa 15 . Other members of this family are multidrug-resistance protein (MRP 1, ABCC1 and MRP2, ABCC2) and breast cancer-resistance protein (BCRP, ABCG2) 16 . These drug transporters act as an outward-directed drug efflux pump and have a function in detoxification and protection against toxic compounds. Oral anticancer agents that are PGP substrates include epipodophyllotoxins, anthracy-clines, camptothecin analogues, and taxanes. In mdr Ia(- -)mice, which lack PGP, the bioavailability of oral paclitaxel indeed significantly increased, with a six-fold increase in the area under the curve (AUC) 17 . Due to the drug efflux pump PGP and the interaction with the formulation vehicle Cremophor EL, the bioavailability of oral paclitaxel is less than 10 . In order to improve its absorption, studies have combined oral taxanes with various inhibitors...

Toxic Agents Drug Overdose Poisons Contrast Media

Ratio Urinary Weak Acid

The first line of treatment of poisons and drug overdoses taken by mouth is an attempt to prevent absorption of these agents from the gastrointestinal tract. Once intestinal absorption has occurred, detoxification, blockade of toxic effects and elimination by metabolism or excretion can be considered as a second line of defense. The kidneys are perfused with plasma at the rate of about 36 liters hour, and about 7 liters of this plasma will be filtered per hour. Thus, an absorbed toxic agent in the blood will traverse the kidney very frequently.

Acceptance of Controlled Drinking

Limited by institutional treatment philosophy and setting. For example, abstinence is the predominant outcome goal prescribed for alcoholics and problem drinkers in American alcoholism treatment programs. A survey of American alcohol treatment agencies found that controlled drinking was considered unacceptable for clients in almost every responding residential program (including inpatient detoxification and rehabilitation services as well as halfway houses). However, almost one-half of the responding outpatient programs reported moderate drinking as appropriate for a minority of their clientele (e.g., drunk driving offenders).

Biopharm 1994 Validation Of Endotoxin Removal From Parenteral Vial Closures

The enhancement of anti-body formation by E. coli lipopolysaccharide and detoxified derivative. J Immunol 1969 102 1411. 37. Taub A, Hart F. Detoxification of pyrogens by hydrogen peroxide in some USP injections. J Am Pharm Assoc 1948 37 246. 44. Goebel W. Studies on the Flexner group of dysentery bacilli. VI. The detoxification of Shigella paradysenteriae by means of periodic acid. J Exp Med 1947 85 499.

Extracellular Precipitation of Metals

Exceeding a solubility product leads to precipitation of an insoluble salt of the reacting species. Sulfide anion (S22) and oxalate anion (C2O4_) are produced by some species of micro-organisms and these anions can form very insoluble salts with heavy metal ions which exhibit very small solubility products as noted by Veglio and Beolchini (1997). Copper phosphate precipitation occurring within the matrix of mycelia of the fungus Penicillium ochro-chloron after 4 days of incubation in shake flask cultures at pH 4, was demonstrated using scanning electron microscopy and energy dispersive x-ray microanalysis (Crusberg et al. 1994). Wrinkled 40-50 mm dia. spheres of insoluble copper phosphate, inferred from EDX analysis, are trapped within the mycelia of the fungus grown for 4 days in aerated cultures in the presence of 100mg l Cu2+. Penicilllium and Aspergillus have been shown to produce extracellular acid phosphatases which correlate with copper removal from solution (Haas et al. 1991...

Other Selected Mycotoxins

After harvest, crop should not be allowed to overwinter in the field as well as subjected to bird and insect damage or mechanical damage. Grains should be cleaned and dried quickly to less than 10-13 moisture and stored in a clean area to avoid insect and rodent infestation (Trenholm et al. 1988). Postharvest mycotoxin contamination is prevalent in most tropical countries due to a hot, wet climate coupled with subadequate methods of harvesting, handling, and storage practices, which often lead to severe fungal growth and mycotoxin contamination of food and feed (Birzele et al. 2000 Phillips et al. 1994). Sometimes contaminated food has been diverted to animal feed to prevent economic losses and health concerns. However, this is not a solution to the contamination problem. Irradiation has been suggested as a possible means of controlling insect and microbial populations in stored food, and consequently, reducing the hazard of mycotoxin production under these conditions reviewed in...

Diet and biotransformation

Irradiation And Contamination

The biotransformation of a toxic compound usually, but not always, results in detoxification. It can, however, lead to the metabolic activation of foreign compounds. The effect of dietary constituents on the metabolism of foreign compounds has been the subject of intensive study for many years. More than two decades ago, the term toxicodietetics was coined for the study of dietary factors in the alterations of toxicity a term that was perhaps ahead of its time. There are a multitude of dietary factors that can affect toxicity. Dietary factors can be associated with the exposure situation, ranging from factors such as palat-ability of the food to the physical volume or rate of food ingestion. Dietary factors can be responsible for producing changes in the body composition, physiological and biochemical functions, and nutritional status of subjects. These factors, and others, can have marked influences on the toxicity of substances. For example, it is customary to fast laboratory...

The BBB a Neurovascular Physiological Unit The Concept

The microvascular endothelium in the BBB serves as an active, energy-dependent barrier, with unique transport properties. In line with their high enzymatic and metabolic activities, brain ECs possess a large number of mitochondria, fuelling an elaborate system of transport proteins (influx and efflux carriers and pumps). The asymmetric distribution of the transporters on the luminal and abluminal EC membrane allows for the vectorial exchange of selected chemicals into or out of the brain. This biochemical-transport barrier ensures a selective permeability of nutrients, neurotransmitter precursors, and xenobiotics. As an enzymatic-barrier, BBB microvascular ECs express a large variety of metabolizing enzymes which serve as biotransformation and detoxification systems, metabolizing and excreting lipophilic endogenous and exogenous chemicals which may have invaded the brain environment.

Genetic Engineering Strategies to Enhance Host Resistance to Mycotoxin Contamination

Genetic engineering may provide innovative solutions to prevent the accumulation of fumonisins in Fusarium-infected maize. One approach currently under development is detoxification of fumonisins by enzymes introduced into maize via genetic engineering. Enzymes that detoxify and degrade fumonisins have been identified from Exophiala spinifera, a black yeast found on moldy maize kernels. The initial steps in fumonisin detoxification are ester hydrolysis followed by oxidative deamination to produce derivatives that lack the free amino function that is believed to be important for toxicity (Blackwell et al. 1999). Genes encoding the deesterification and deamination enzymes have been cloned

The Physiological Differences of Addiction

Of withdrawal symbolizes the conflict between the artificial substance and the natural body. If the drug is suddenly removed from the organism, it has to readjust. Unpleasant symptoms are experienced, but ultimately the capacity of the body to right itself prevails and balance is restored. The body is imagined as a self-healing entity which, even after years of abuse, retains the ability to detoxify and rebalance itself. Withdrawal then becomes not only a physiological readjustment but a profoundly meaningful process of purification and restitution.

Scientific Basis And Implications

The extrapolation of animal exposure data to human exposure levels is uncertain both qualitatively and quantitatively. The nature of the hazard may change with dose. Not only is the equivalent dose estimate in animals and humans problematic in comparative pharmacokinetics, the metabolism of the chemical may change as the dose changes. Whereas high doses can overwhelm detoxification pathways, the effects may be unrelated to those seen at low doses (WHO, 1995).

Hepatic Encephalopathy Is A Disorder Of Astrocyte Function Resulting In A N E U R O P S Y C H I At R I C Syndrome

Brain Leucine Glutamate Flux Astrocyte

Ginated, and a prominent nucleolus is often observed. Lipofuscin deposits may be present, and the amount of the astrocyte-specific protein glial fibrillary acidic protein (see Chapter 2) is decreased. Neurons appear structurally normal. All the foregoing histopathological changes have been reproduced in vitro by acutely or chronically applying ammonium chloride to primary astrocyte cultures. As mentioned earlier, detoxification of ammonium is an ATP-requiring, astrocyte-specific reaction catalyzed by glutamine synthase (see Fig. 3.12). It is therefore not surprising that excess ammonia perturbs energy metabolism indeed, ammonia stimulates glycolysis (McKhann and Tower, 1961) whereas it inhibits TCA cycle activity (Muntz and Hurwitz, 1951). In addition, ammonia markedly decreases the glycogen content of astrocytes. A key function of astrocytes is to remove synapti-cally released glutamate. A large proportion of glutamate is transformed to glutamine through an energy-requiring process...

Glutathione Reduced GSH and oxidized GSSG

Glutathione (GSH, -glutamylcysteinylglycine) and its oxidized form (GSSG) (Figure 10. 7) together form the first line of defense against the cellular protection against reactive oxygen species (22,23,106,107). They carry out their protective functions by reducing ROS via their thiol groups, and therefore are involved in a variety of processes in the cellular systems that involve generation of free radicals such as detoxification of xenobiotics, reduction of hydroperoxides, and synthesis of leukotrienes and prostaglandins (106,107). The reducing power

Normal Physiology and Function

Astrocytes serve some essential functions for glutama-tergic neurons and the glutamate synapse. The glutamate synapses involve the coordination between the presynaptic terminal of the axons, postsynaptic membrane, and surrounding astrocytes. The processes of astrocytes located around synapses possess high-affinity glutamate and GABA transporters that remove excess released neurotransmitters in order to limit neuronal excitation. Additionally, glutamate synthetase, found only in astrocytes, catalyzes the conversion of glutamate to glutamine, thereby providing neighboring neurons with the substrate for the production of glutamate. Therefore, glutamate syn-thetase also functions to detoxify neurotoxic levels of glutamate as well as ammonia. Glutamate dehydro-genase, another enzyme found in astrocytes, catalyzes the formation of glutamate from a-ketoglutarate and ammonia. Therefore, astrocytes are able to directly produce glutamate. Astrocytes may also modulate neuronal electrical...

Biological Function Of Phenolic Phytochemicals

Emerging research into the biological functionality of phenolic phytochemicals also strongly suggests their ability to modulate cellular physiology both at the biochemical physiological and at molecular level. Structural similarities of phenolic phytochemicals with several key biological effectors and signal molecules have been suggested to be involved in induction and repression of gene expression or activation and deactivation of proteins, enzymes, and transcription factors of key metabolic pathways (27,33-35). They are believed to be able to critically modulate cellular homeostasis as a result of their phys-iochemical properties such as size, molecular weight, partial hydrophobicity, and ability to modulate acidity at biological pH through enzyme (dehydrogenases) coupled reactions. As a consequence of many modes of action of phenolic phytochemicals they have been shown to have several different functions. Potential anticarcinogenic and antimutagenic properties of phenolic...

Biological Removal Biotransformation and Biosorption of Metal Ions from Contaminated Wastewater

Whereas solid organic and inorganic material in wastewater or sludge can be removed by sedimentation, soluble organic pollutants and xenobiotics should be eliminated from the aqueous environment by microbial mineralization or anaerobic degradation to gaseous products, with a varying portion (5 -50 ) being used as substrates for bacterial growth. Most of the inorganic components present in wastewater are soluble and are ionized. Trace amounts of many cations (e.g., Na+, K+, Ca2+, Fe2+, Ni2+, Co2+, Mn2+, Zn2+, etc.) and anions (e.g., PO3-, Cl-, S2-) are essential micronutrients for bacterial growth. Other cations such as ammonia may also be required for bacterial growth, but the surplus amount must be oxidized to nitrate, and the nitrate denitrified to gaseous nitrogen, for N elimination from wastewater. Under anaerobic conditions sulfate is reduced to sulfide, low amounts of which are required for growth of bacteria. The sulfide not required for growth is toxic for bacteria if present...

Cpg Island Hypermethylation Changes During Prostate Cancer Initiation And Progression

Prostate Cancer Disease Progression

In 1994, Lee et al. demonstrated that hypermethylation of CGI sequences within the regulatory region of GSTP1, which encodes the pi-class glutathione S-transferase (GST) enzyme, is an extremely frequent feature of human prostate cancer (49, 50). Since that initial study, numerous groups have independently corroborated these findings using a wide array of techniques applied to numerous prostate cancer DNA sources, including prostatectomy specimens, prostate autopsy specimens, prostate biopsy specimens, prostate secretions, and various bodily fluids from prostate cancer patients. Furthermore, GSTP1 CGI hypermethylation appears to be an extremely specific finding for prostate cancer as it is not characteristic of normal prostates or benign prostatic hyperplasia. The GST enzymes catalyze the detoxification of carcinogens and reactive chemical species via the conjugation of glutathione. It has been hypothesized that loss of this detoxification agent in prostate cells might make them...

Applications of germfree animals Surgical application

In an intestinal tract of a 'normal' animal, the bacterial cells outnumber the cells of the whole body. This means that an enormous metabolic capacity is present in the intestinal tract. Detoxification of a broad variety of toxic products occurs by the normal microflora. With the help of gnotobiotic animals this phenomenon can be investigated in relation to the quality of the microflora.

Metabolic Function and Essentiality

Some of the most important and characteristic functions of NAD manifest in the principal cellular catabolic pathways, responsible for liberation of energy during the oxidation of energy-producing fuels. NADP, however, functions mainly in the reductive reactions of lipid biosynthesis, and the reduced form of this coenzyme is generated via the pentose phosphate cycle. NAD is essential for the synthesis and repair of DNA. NAD has, in addition, a role in supplying ADP ribose moieties to lysine, arginine, and asparagine residues in proteins such as histones, DNA lyase II, and DNA-dependent RNA polymerase, and to polypeptides such as the bacterial diphtheria and cholera toxins. In the nucleus, poly (ADP ribose) synthetase is activated by binding to DNA breakage points and is involved in DNA repair. It is also concerned with condensation and expansion of chromatin during the cell cycle and in DNA replication. Niacin status affects the level of ADP ribolysation of proteins. A high level of...

Eukaryotic Cell Structure And Function

In eukaryotes, the ribosomes line a folded membrane structure called the endoplasmic reticulum (ER), which occupies a large portion of the cytoplasm. ERs serve as channels to transport newly synthesized substances within a cell. The part studded with ribosomes, called the rough ER, is responsible for the synthesis of proteins, including enzymes. Another portion of the ER, the smooth ER, lacks ribosomes. The smooth ER is associated with synthesis of lipids and the detoxification of lipid-soluble toxins. The liver has abundant smooth ER. It is the location of the enzyme complex cytochrome P450 system, which is responsible for much of the liver's detoxification activity as well as other biotransformation functions (see Section 18.5) Other vesicles, including lysosomes, remain in the cytoplasm. Lysosomes contain enzymes that can digest particles taken in by endocytosis or, interestingly, can be used by the cell to commit suicide, when the cell is damaged or otherwise unneeded. Other...

Stereoselectivity and Toxicity The Rofe of Biotransformation

Metabolism of the cytostatic drug cyclophosphamide (CP Fig. 1) involves hydroxylation at the C-4 position by cytochrome P450. Subsequently, a number of detoxification reactions can occur (oxidation to the 4-keto derivative, dechloroethylation, formation of a carboxylic acid). The phosphoramide mustard resulting from spontaneous decomposition of 4-hydroxy-CP is thought to be the cytotoxic chemotherapeutic species. The chiral nature of the phosphorus atom resulted in a twofold greater therapeutic index (LD ED ) for the S-(-)-enantiomer (against the ADJ PC6 plasma cell tumor in mice) without detectable differences in metabolism by rat liver microsomes (Cox et al., 1976). Several studies revealed considerable species differences in the metabolism of CP enantiomers, both in the initial 4-hydroxylation and in the later oxidative detoxification pathways (Farmer, 1988). Preliminary studies in man showed that the geometrical isomer iphosphamide undergoes more stereoselective metabolism than CP...

Ecogenetics Individual Variation in Susceptibility to Environmental and Chemical Agents

Biochemical and molecular techniques are being used to develop new genetic markers of host susceptibility to environmental and chemical agents. To cause poor health, many chemicals must be activated by enzymes to intermediates that attack DNA (as appears to be the case in many environmentally-induced cancers and birth defects). Other enzyme systems detoxify potentially toxic compounds, and variation in the genes that specify the sequence of enzymes involved in these biotransformation steps can result in people with similar exposures having very different disease risks. An example of this type of gene-environment interaction affecting health outcomes is deficiency in the enzyme glutathione S-transferase (GST), which is believed to be an important predisposing factor in the development of some environmentally-induced cancers. About 45 percent of persons of European ancestry lack detectable activity of a particular form of GST. Several studies examining GST levels in lung tissue suggest...

Molecular Mechanisms In The Generation And Propagation Of Aberrant Dna Methylation Patterns In Prostate Cancer

Conjugated oxidant species that would then have to be transported out of the cell or metabolized further into inert compounds. Surprisingly, however, the GSTP1 expressing LNCaP clones exhibited less clonogenic survival than the control LNCaP cells (94). In a similar experiment, Diah et al. overexpressed GSTP1 and or MRP1, a glutathione-conjugated toxin active transporter, in MCF7 breast cancer cells, which normally do not express either of these proteins. They then treated these cells and MCF7 wild type controls with the toxin 1-chloro-2,4-dinitrobenzene (CDNB), and found that a) MCF7 cells overexpressing MRP1 alone had three to four fold increased resistance to CDNB cytotoxicity associated with a 10 fold increase in efflux of the glutathione conjugate of CDNB as compared to wild type MCF7 cells, b) MCF7 cells overexpressing both MRP1 and GSTP1 showed increased formation and a commensurate increase in efflux of the glutathione conjugate of CDNB and increased resistance to short-term...

Amphetamines and Related Drugs

Amphetamines are more toxic than cocaine and, when abused, cause worse problems. The body has a great capacity to metabolize and eliminate cocaine the liver can detoxify a lethal dose of cocaine every thirty minutes. It cannot handle amphetamines as efficiently. At the same time, people can establish stable relationships with amphetamines more easily than they can with cocainc, probably because the intensely pleasureful but very short effect of cocaine is more seductive and invites repetitive dosing.

Feeds Used And Conversion Rates

Actual conversion rates are affected by product produced and level of technology involved in the production system, and particularly by the two related factors of type of digestive system and type of diet. Ruminant species, including cattle, sheep, goats, and buffaloes, typically have lower conversion rates, i.e., produce less product per unit of total feed intake than monogastric species such as pigs and poultry, but the diets of ruminant species on average contain a much higher proportion (often 100 ) of human-inedible feeds. This is possible because of the four-compartment ruminant stomach, including the large rumen where microbial digestion takes place. Rumen microorganisms break down plant materials with high fiber content that monogastric animals (including humans) cannot digest, providing energy for the ruminant host. The microorganisms also synthesize essential amino acids from nonessential amino acids and nonprotein nitrogen, contributing to the protein nutrition of the host...

Seizures in the Alcohol Abuser

If the clinical presentation and evaluation are consistent with alcohol withdrawal seizures, and the patient remains stable and seizure-free for several hours, the patient may be discharged and referred for detoxification. Outpatient detoxification with a benzodiazepine regimen is most appropriate for patients with mild to moderate withdrawal symptoms, no significant medical or psychiatric problems, no concurrent drug use, and no history of DTs. Patients with more than two seizures should be admitted.

Effects on Particular Organs or Organ Systems

As mentioned above, particular toxins will tend to target particular organs or organ systems. The liver and the kidney are common targets of toxic activity because of their role in detoxification and their large blood flow. The skin and eyes, lungs, and digestive tract are vulnerable to the more reactive toxicants, as they are the sites of first entry to the organism. The nervous system has both unique protection and vulnerability. Liver The liver receives almost all the venous blood flow prior to its return to the heart and lungs. All of the blood from the stomach and intestines go directly to the liver. Thus, substances absorbed in the GI tract may be biotransformed before reaching other organs. Although the liver detoxifies most compounds, some are converted to more toxic forms. As the generator of most of the bioactivated compounds (see Section 18.5), the liver is also the site of first and most concentrated contact. The liver is the main site of toxic damage for a number of...

Recombinant vaccines expressing tumor associated antigens

Autologous tumor cells are used in various strategies of active specific immunotherapy. A real disadvantage of this approach is that it is logistically very demanding and that a relatively large amount of tumor tissue is required for the preparation of vaccines. Because of this, some groups were investigating the application of allogeneic tumor cell vaccines. One such vaccines is Melacine (Corixa-Montana) consisting of lyophilized lysates of two melanoma cell lines, MSM-M-1 and MSM-M-2, admixed with the immunological adjuvant Detox-PC (Corixa-Montana) immediately before use. A Phase I study in 19 patients with metastatic melanoma proved the feasibility of immunization against melanoma-associated antigens in 50 of the patients and elicited a 29 objective clinical response 46 . The follow up Phase II trial in 25 patients with metastatic melanoma demonstrated a response in 5 patients and immunomonitoring revealed that an increase in precursors of cytolytic T cells against melanoma cells...

Dietary Selenium Absorption and Mechanisms of Incorporation of Selenium into Selenoproteins

Selenide represents the 'crossroads' of selenium metabolism, from which it may either be committed to specific selenoprotein synthesis or be removed from the body by urinary excretion pathways that involve its detoxification by methylation to methyl selenides, of which the largest fraction is usually trimethyl selenonium. If used for selenoprotein synthesis, selenide combines with a chaperone protein, and the first metabolic step is its conversion to selenophosphate by the ATP-requiring enzyme

Mutualistic Interactions

Bacteria that detoxify fungal cell membrane disrupting compounds produced by bacterial pathogens of fruit bodies (see above) may also be considered as mutualists of basidiomycetes. Tsukamoto et al. (2002) isolated several tolaasin-detoxifying strains from wild Agaricales. Perhaps the presence of tolaasin-detoxifying strains on wild mushrooms explains why P. tolaasii is much more frequently isolated from cultivated mushrooms than from wild ones (Bessette, 1984). More detailed investigations are needed to understand the nutritional requirements of the antagonists of P. tolaasii. If they are preferentially selected by the fungus, for example via a resistance to antibacterial compounds and are growing on fungal exudates, this would be true mutualism.

Hazards of Alcohol

Alcoholism is associated with an increased prevalence of psychiatric disorders, although symptoms of anxiety and depression may often abate following detoxification and a period of abstinence. Whether alcoholism is a cause or a consequence of other mental disorders continues to be debated. An important longitudinal study challenges the view that alcoholism is but a symptom of preexisting emotional problems with the finding that the mental health of nonalcoholics and future alcoholics does not differ significantly in childhood (Vaillant).

Species Differences in Amino Acid Metabolism

Metabolic pathways for most amino acids are generally similar between microorganisms and animals, but important differences do occur. For example, N-acetylglutamate is an intermediate of and an allosteric activator for arginine synthesis in microorganisms and animal cells, respectively. 2,5 Second, deiminase plays a significant role in microbial arginine degradation to form citrulline and ammonia animal cells, however, lack this pathway. Third, the conversion of proline into pyrroline-5-carbox-ylate is catalyzed by NAD(P)+-dependent proline dehy-drogenase in microorganisms, but by oxygen-dependent proline oxidase in animal cells. Regarding differences among animals, most mammals (except for cats and ferrets) can convert glutamine, glutamate, and proline into citrulline in enterocytes, whereas birds do not. Similarly, ammonia detoxification pathways differ remarkably between ureotelic and uricotelic organisms.

Protective Role of Astrocytes

Astrocytes may protect dopaminergic neurons from degeneration by metabolizing dopamine and scavenging oxygen free radicals that are associated with dopamine metabolism. Glutathione peroxidase and catalase are involved in the detoxification of H2O2 by astroglial cells.

Functional and Structural Effects

Disruptions of neuronal cell homeostasis occur when natural protective mechanisms fail to detoxify and eliminate a potentially hazardous chemical substance before it causes tissue damage. A neurotoxic chemical is defined as a substance that is directly and or indirectly capable of the following (1) altering the integrity of nerve cell membranes, thereby affecting neuronal excitability, neurotransmitter release, and synaptic activity of neurons (2) disturbing the flow of axoplasm, thereby interfering with the transport of neurotransmitters and nutrient substances along the axon to and from the cell body (3) disrupting cellular respiration processes (4) disrupting protein synthesis (5) affecting neuronal functions indirectly by damaging Schwann cells and peripheral myelin, oligodendrocytes, and central myelin and or disrupting the normal functioning of astrocytes and microglia and (6) disturbing extracellular fluid volume and flow by damaging capillary endothelium,...

Oral ingestion studies

The bioactivity of a toxicant ingested varies with the frequency, presence of food, and the makeup of the food, such as amount of purified sugar, fiber, high protein, or high fat. The different pH conditions of the gastrointestinal tract affect the ionization of weak organic acids and bases. Following absorption in the gastrointestinal tract, the bioactive chemical is translocated to either the lymphatic system or the portal circulation. The portal circulation directs the chemicals to the liver, and many of the chemicals are excreted by the liver as bile. Because the bile empties back into the intestine, a cycle involving translocation of the chemical from the gastrointestinal tract to the liver and via the bile back to the intestine occurs. This cycle is known as enterohepatic circulation. Ingestion of chemicals from the gastrointestinal tract and enterohepatic cycle exposes the liver to those concentrations of the agent that would not be obtained by other exposure routes, such as...

Suitability and Limitations of Primary Cells as Physiologic Models

Growing numbers of hits from primary high-throughput discovery programs generate the need for early, fast and robust lead candidate identification. In order to avoid creating a bottleneck at this stage, decisions on compound selection rejection must be made before animal testing, with the required throughput and minimal substance use. For the accurate prediction of compound specificity and related toxicity, these assays must rely on physiological models that clearly reflect the situation in the target tissue. Miniaturized culture systems ofprimary cells or tissue samples - preferably of human origin - should best suit this purpose. Indeed, the human primary hepatocyte is one of the most extensively used in-vitro models in toxicology because of its central role in drug metabolism and detoxification and as a sensitive detector for generalized cytotoxicities relevant to other organs 1 . Since human hepatocytes are obtained from donor livers not used in transplantation, the availability...

Receptivity And Implantation Adhesion Cascade

Global gene profiling using high-density microarray technology has identified genes that either increase or decrease during the window of implantation. Comparison of endometrial tissue between late proliferative phase and secretory phase human endometria identified 323 genes that increase and over 370 genes that decrease by at least twofold. 10 Modulated genes include cell-surface proteins receptors, ECM molecules, secretory proteins, immune modulators cytokines, cytoskeletal proteins, transporters, and transcription factors, as well as proteins involved in cholesterol trafficking, prostaglandin biosynthesis, detoxification, cell-cycle regulation, signal trans-duction, and other cellular functions. About 20 of the changes were attributed to genes encoding cell-surface receptors, adhesion and ECM proteins, and growth factors, 10 including markers of uterine receptivity in humans such as glycodelin and OPN, stromal cell-specific insulin growth factor-binding proteins-1 and -2,...

Resolutions via Derivatization of Epoxides

Metabolic epoxidation of carbon-carbon double bonds in alkenes and arenes is a fundamentally important biotransformation of foreign compounds. The primary epoxide (oxirane) metabolites formed generally undergo further biotransformation to more polar and readily excreted metabolites via conjugation with glutathione or epoxide-hydrolase-mediated hydrolysis to diols. Thus, epoxidation can be considered the first step in a metabolic detoxification scheme. On the other hand, epoxidation is also a

Interactions between Saprotrophic Basidiomycetes and Bacteria

Bacteria play an important role in the functioning of lignocellulose-degrading basidiomycetes. They can have a negative effect on fungal growth and activity as they are potential competitors for low-molecular weight compounds released by extracellular fungal enzymes. There are also some indications of bacterial mycophagy. On the other hand, basidiomycetes may benefit from the presence of bacteria, in particular with respect to nitrogen supply and detoxification of mycotoxic compounds.

A continuous and unavoidable threat

Accidental, but unavoidable, production of ROS occurs during the passage of electrons along the mito-chondrial electron transport chain. Leakage of electrons from the chain leads to the single-electron reduction of oxygen, with the consequent formation of superoxide. This can be regarded as a normal, but undesirable, by-product of aerobic metabolism. Around 1-3 of electrons entering the respiratory chain are estimated to end up in superoxide, and this results in a large daily ROS load in vivo. If anything increases oxygen use, such as exercise, then more ROS will be formed, and oxidant stress may increase owing to a pro-oxidant shift. Significant amounts of ROS are also produced during the metabolism of drugs and pollutants by the mixed-function cyto-chrome P-450 oxidase (phase I) detoxifying system and as a consequence of the transformation of xanthine dehydrogenase to its truncated oxidase form, which occurs as a result of ischemia. This causes a flood of superoxide to be formed...

Neurotransmitter Transporters and Receptors 1 Glutamate Transporters

Glutamine synthesis is important for the detoxification of ammonia. During hepatic encephalopathy and other hyperammonemic states, the ability of the brain to fix excess blood levels of ammonia produced may be limited. Ammonia inhibits glutamine efflux from astrocytes, which probably contributes to astrocyte swelling and alteration of calcium homeostasis. The reduction of the extracellular space following astrocyte swelling may result in an increase in the extracellular concentration of ions, especially calcium that could affect neuronal excitability. Swollen astrocytes also release glutamate, which might also contribute to excitotoxicity. These data suggest that glial glutamate transporters provide the majority of functional glutamate transport and are essential for both maintaining

Sage Uses In Human Genome Mining And Annotation

Recently, hierarchical clustering was used to analyze SAGE data, comparing normal lung epithelial cells and non-small cell lung cancers. One hundred fifteen transcripts were identified that clearly distinguished both groups (i.e., normal and tumors), and furthermore, it was possible to differentiate non-small cell lung cancer histological subtypes. Adenocarcinomas were characterized by high level of expression of small airway-associated or immunologically related proteins, and the p53 target genes p21 (CDKN1A) and 14-3-3 were consistently underexpressed. Squamous cell carcinomas were characterized by overexpression of genes involved in detoxification or antioxidation. These observations were validated by real-time PCR analyses in larger numbers of samples, importantly indicating that an analysis of a limited number of SAGE libraries was sufficient to provide information significant for defining tumor-specific molecular signatures, which could then be extrapolated to a larger scale...

Physiology and function

Detoxification is one of the major functions of the liver, and important enzyme systems exist to break down substances that are toxic to the body. One of the main systems is the cytochrome p450 system, which aides in oxidative break down of toxic metabolites. Certain medications can induce the cytochrome p450 system, as they are toxic, or inhibit the enzyme system and thereby influence the metabolism of other drugs. This can be very important clinically as patients with histories of substance abuse (i.e., alcohol) will have an induced cytochrome p450 system, which increases the metabolism of pain medications, and some anesthetics affecting their clinical management.

Amino Acid Degradation

Thus, plasma levels of ammonia (primarily NH+) must be precisely regulated. Syntheses of urea (via hepatic and intestinal urea cycles) and uric acid (via hepatic purine metabolism) represent the major pathways for ammonia detoxification in mammals and birds, respectively. Hepatic ureagenesis is subject to both short- and long-term regulation 1) availabilities of substrates and N-acetylglutamate, and 2) adaptive changes in the amounts of urea cycle enzymes. 5 Glutamine synthetase is a major regulatory enzyme for uric acid synthesis in uricotelic species.

Methods For Immobilization

Enhanced catalyst stability due to protection by the cell membrane and the local microenvironment, and the ability to catalyze multistep enzymatic reactions, particularly those using cofactors that are otherwise difficult to regenerate. Disadvantages include the following the possibility of side reactions and hence less pure products and both substrate and product must be small enough to pass through the gel particles. Currently, immobilized cells are used either to catalyze simple conversions such as iso-merization or as growing immobilized cells to produce primary metabolites, for example, amino acids. Immobilized living cells can also be used to detoxify waste materials, for example, to remove nitrates from drinking water and to remove phenols from industrial wastewater (4).

Conclusions and Novel Trends in Liver Tissue Engineering

Until now, the development of liver tissue engineering has focused primarily on generating functional liver constructs for in-vivo use (replacement of diseased liver), or on the engineering of bioartificial hybrid BAL systems for detoxification. Novel types of scaffold that have been designed more recently for hepatic constructs, are well suited not only for implantation but also as matrices for engineering liver tissue-equivalents for basic and applied research, including in-vitro models for drug discovery and testing (e.g., for developing hepatic vaccines).

Alcoholic Liver Disease

In the abdominal cavity, and the syndrome of hepatic encephalopathy, which is due to inadequate hepatic detoxification of substances in the visceral blood that is shunted around the liver. The risk of developing alcoholic cirrhosis is dependent upon the amount of alcohol exposure independent of the presence or absence of malnutrition. For example, a study of well-nourished German male executives found that the incidence of alcoholic cirrhosis was directly related to the daily amount and duration of alcohol consumption, such that daily ingestion of 160 g alcohol, equivalent to that found in a pint of whisky, over a 15-year period predicted a 50 risk of cirrhosis on liver biopsy. Other worldwide demographic data indicate that mortality rates from cirrhosis of the liver can be related to national per capita alcohol intake. These studies have defined the threshold risk for eventual development of alcoholic cirrhosis as 6 drinks per day for men, and about half that for women.

Liver Disease Applied Physiology

The liver is the largest organ in the body receiving 30 of cardiac output. The majority of nutritional, haematological and detoxification metabolism occurs in the liver, including the breakdown or excretion of many anaesthetic drugs. Other physiological roles of the liver include the manufacture of proteins, lipoproteins and carbohydrates which includes the clotting factors and the proteins to which most anaesthetic drugs are bound. Globulins are not produced in the liver. The liver also acts as a store for vitamins, minerals and carbohydrates. In the presence of significant liver disease, all these processes become disturbed.

Potential Importance of Phytoestrogens to Human Health Molecular Mechanisms of Action

Consumption of Brussels sprouts (300g day of cooked sprouts) for 1 week has been shown to increase rectal glutathione S-transferase -a and -k isoenzyme levels. Enhanced levels of these detoxification enzymes may partly explain the epidemiological association between a high intake of glucosinolates in cruciferous vegetables and a decreased risk of colorectal cancer. It is likely that genetic polymorphisms and associated functional variations in biotransformation enzymes, particularly in glu-tathione S-transferases, will alter the cancer preven-tative effects of cruciferous vegetables. Isothiocyanates can prevent the formation of chemical carcinogen-induced tumors of the liver, lung, mammary gland, stomach, and oesophagus in animal models. The anticarcinogenic effects of isothiocya-nates may be mediated by a combination of mechanisms, including inhibition of carcinogen activation by cytochromes P450 This could be achieved by both direct inhibition of enzyme catalytic activity and...

TABLE 341 Psychological Characteristics of Chronic Pain Patients

The following set of historical inquiries may prove helpful in the ED. The patients should be asked to describe the nature of the current pain, initiating and exacerbating or relieving factors. Other useful information includes determination of the chronic nature of their pain, quantification of similar episodes, and sources and modes of treatment, including medications and dosages for physician-prescribed, over-the-counter, or alternative medications. Outcomes of previous therapeutic efforts and the effect of the condition on the patient's functional status are also important. Addiction to drugs or alcohol or experience with detoxification programs should also be noted. Finally, a review of systems should be done to rule out any other conditions. Substance abuse is a frequent problem in chronic pain patients. Patients referred to chronic pain clinics meet Diagnostic and Statistical Manual of Mental Disorders, third revised edition (DSM III-R) criteria for active substance abuse...

Arginine Citrulline Ornithine and Proline Figure

Arginine is a nitrogen-rich amino acid because it contains three nitrogen atoms and is the precursor for nitric oxide (NO). The conversion to NO is catalyzed by the enzyme nitric oxide synthase (NOS), and results in coproduction of the amino acid citrulline. Depending on its site of release, NO exerts several functions including stimulation of the pituitary gland, vasodilation, neurotransmission, and immune modulation. Arginine is also a precursor for urea synthesis in the urea cycle, which has an important function in the detoxification of ammonia and excretion of waste nitrogen from the body. A full urea cycle is only present in the liver, but the arginase enzyme that converts argi-nine to urea and ornithine is to a limited extent also found in other tissues and cells, such as brain, kidney, small intestine, and red blood cells. Ornithine is utilized for the formation of proline, polyamines (putrescine, spermine, and spermidine), glutamic acid, and glutamine. Arginine is involved in...

Toxic Epidermal Necrolysis

The pathogenesis is poorly understood and may be partly an immunologic and partly a genetic predisposition. The tendency to develop TEN may be linked to a highly specific genetic defect in the detoxification of the culprit drug or its reactive metabolites. 9 Human lymphocyte antigen (HLA) typing has also suggested a possible genetic predisposition.

TABLE 123 Phenolic Substances

Thiosulfate plays a key role in detoxification of cyanide. Thiosulfate originates from sulfate metabolism. More than 800 phenolic substances are known in plants. Such compounds contribute to the bitter taste, flavor, and color of foods. Table 12.3 lists some classes of phenolic substances. Most of the phenolic substances are devoid of acute toxicity. Methods are available to detoxify them.

Differential Diagnosis

The diagnosis of thiocyanate toxicity should be considered in the patient receiving a sodium nitroprusside infusion who becomes encephalopathic. Thiocyanate, the product of metabolic detoxification of cyanide, accumulates in patients with renal insufficiency and results in encephalopathy without the development of lactic acidosis or impaired oxygen utilization.6 Levels of thiocyanate greater than 100 mg L support the diagnosis of toxicity.6

Control Of Bile Acid Transport And Metabolism

An important mechanism toward controlling bile acid levels within cells is to adjust the cellular uptake or efflux of bile acids by regulating the expression and or activity of uptake and efflux proteins, as discussed in detail below. It should be noted, however, that additional mechanisms are also operational in preventing intracellular bile acid concentrations from reaching toxic levels. One such mechanism is to regulate the de novo synthesis of bile acids according to the existing intracellular bile acid content. To reduce bile acid synthesis, the expression levels of the key CYP enzymes involved in de novo bile acid synthesis (i.e., CYP7A1, CYP8B1, and CYP27A1) are suppressed.42 Furthermore, expression levels of several phase II enzymes that in addition to their role in drug detoxification may convert bile acids into less toxic and more hydrophilic derivatives are induced in response to elevated levels of bile acids.43 These metabolizing enzymes include uridine 5'...

Solidstate bioprocessing

Resulted due to the hydrolysis of ellagotannins by tannin hydrolyzing enzymes produced by the fungus. Further, it is suspected that phenolic enrichment could also occur through contribution from the growing fungal species. The endogenous phenolics present in the fruit wastes could be toxic to the growing fungus. In an attempt to adapt and utilize the substrate for growth, the fungus could be detoxifying the phenolics biochemically using a variety of enzymatic systems present in the fungus. The fungal detoxification can occur by a variety of mechanisms including methylating or demethylating the pheniolic ring, or by hydroxylation (219,220). Recent studies have shown methylated phenolic phytochemicals have excellent antibacterial properties against Gram-positive bacteria (221). Hydroxylation of the phenolic ring by the fungal system during its growth increases antioxidant properties (19) and therefore, phenolics resulting from biotransformation occurring during the solid-state...

Animal Models For Pharmacological And Toxicological Studies

The majority of drug metabolism takes place in the liver where transcription factors including pregnane X receptor (PXR) and constitutive androstane receptor (CAR), both nuclear hormone receptors, regulate the expression of phase I cytochrome P450 oxygenases (CYPs), phase II UDP-glucuronosyltransferases (UGTs), and phase III transporters such as multidrug resistance-associated proteins (MRPs) and organic anion transporting polypeptide 2 (OATP2) for elimination and detoxification in response to xenobiotics or drugs (Bock and Kohle, 2004 Sonoda et al., 2003). The activities of these nuclear receptors are regulated by binding to structurally distinct xenobiotics through their respective ligand-binding domains.

Fulminant Hepatic Failure

Intracranial hypertension secondary to cerebral edema frequently complicates the course of patients with fulminant hepatic failure. The devastating effects of cerebral edema contribute to the high mortality of this condition, with cerebral edema noted in 50-80 of cases at autopsy. Although the progressive obtundation of fulminant hepatic failure may be confused with hepatic encephalopathy, important differences exist. The rapid demise associated with fulminant hepatic failure results from a combination of cytotoxic and vasogenic edema (Fig. 10), whereas edema is not seen in cirrhotic patients dying in hepatic coma. The pathogenesis of cerebral edema formation in fulminant hepatic failure has been attributed to the detrimental effects of ammonia. Due to an incomplete urea cycle in the brain, astrocytes detoxify ammonia to glutamine. Excessive production of glutamine leads to excitotoxic neuronal damage and astrocytic swelling, although osmotic compensation occurs in chronic liver...

Individual Variability

Young animals are typically 1.5 to 10 times as sensitive to toxins as adults, possibly due to underdeveloped immunity or detoxification mechanisms. Malathion is about 28 times more toxic to newborn rats than to adults. However, this is not always the case. DDT is about 20 times less toxic to newborns, and Dieldrin was about 4.5 times less toxic. The young may absorb differently, and their blood-brain barrier is less efficient.

Other Phytochemicals of Interest

Phytochemicals extracted from licorice (Glycyr-rhiza glabra L.) include glycyrrhetic acid, glycyr-rhizic acid (the sweet principle of licorice), and an active saponin glycyrrhizin (a 3-O-diglucuronide of glycyrrhetic acid). In rats, dietary supplementation with 3 licorice elevated liver glutathione transfer-ase activity, suggesting a potential detoxification and anticancer effect of these phytochemicals because glutathione transferase catalyses the formation of glutathione conjugates of toxic substances for elimination from the body. Antibacterial, antiviral, antioxidant, and antiinflammatory effects have also been reported for these compounds. Indeed, glycyrrhizin has been reported to inhibit HIV replication in cultures of peripheral blood mononuclear cells taken from HIV-seropositive patients.

Pharmacogenetics Of Drugmetabolizing Enzymes

Detoxification of environmental constituents including dietary components, no selection pressure is put on the conservation of functionally active genes subjects lacking one or several types of these genes usually have a normal physiological phenotype. The major part of the interethnic differences in the genetic constitution of these genes is a result of incidental mutations in the genes, amplified in certain areas because of population expansion. The lack of endogenous function of the gene products has thus allowed this extensive heterogeneity with respect to allelic distributions in different parts of the world.

Genetic control of leaf senescence and fruit ripening

Phloem during senescence and are regarded as the main transportable amino acids (Buchanan-Wollaston and Ainsworth, 1997). ATP sulphurylase is involved in the biosynthesis of cysteine and methionine. It has been proposed that during senescence the up-regulation of ATP sulphurylase leads to a subsequent increase in the cysteine pool. Cysteine is the precursor for glutathione biosynthesis, a major antioxidant, which, in addition to its role in the recovery of ascorbate and scavenging of reactive oxygen species (ROS), also acts in the transport and storage of sulphur (Rennenberg, 1982), the regulation of cell division and development (Earnshaw and Johnson, 1985), the regulation of gene expression and signalling (Wingate et al., 1988 Herouart et al., 1993 Moran et al., 2001) and the detoxification of xenobiotics and heavy metals (Delhaize et al., 1989 Halliwell and Gutteridge, 1986 Timmerman, 1989).

Hospitalized Patients

The management of opioid dependent individuals hospitalized for medical or surgical reasons remains controversial. It is generally agreed that detoxification from opioids during the acute course of a medical illness is usually unsuccessful. Alleviation of withdrawal symptoms should be the goal of therapy. Daily administration of a verified dose of methadone orally (or half the verified dose intramuscularly if the patient is to take nothing by mouth) is recommended to inhibit withdrawal symptoms and reduce craving. This applies only to individuals who are actively enrolled in a methadone maintenance program and in whom the dose can be verified externally. The habitual user who is not on methadone maintenance therapy can receive methadone 20 mg by mouth (PO) or 10 mg IM. These dosages should inhibit withdrawal symptoms but not induce euphoria. No methadone should be administered to the habitual user until the appearance of withdrawal symptoms. Occasionally, patients will present to the...

Saprotrophs of Attached and Fallen Wood and Litter

Senescent leaves together with resident mycoflora will eventually fall to the litter or soil surface. Some phylloplane fungi (Aurobasidium spp. and Cladosporium spp.) may persist, and some may even complete their (sexual) life cycle during this phase. However their consequential net decomposition may be very low. Litter is rapidly colonized by certain soil-inhabiting fungi (e.g., Penicillium, Trichoderma, and Fusarium spp.), which appear to cause little direct litter decomposition, but may produce significant indirect effects, such as synergistically increasing decay rates with litter-agarics. The early ruderal strategists are progressively replaced by saprotrophic communities, which decay leaf surface waxes, pectins, and the lignocellulose complex itself. Later significant decay stages are associated with the litter-basidiomycetes, especially agarics such as Mycena, Marasmius, and Clitocybe, which form a significant portion of fungal biomass within litter. Such species are capable of...

Specifying External Conditions

The measurement of power per unit mass of biological material entering a food chain (Figure 1) is dependent on the type of material (fuel) is supplied and what specific device (i.e., which organisms) release the energy. A fundamental question is whether there are species of creature evolved to digest bark at the same rate as other organisms might digest seeds Or, has some irreversible change occurred when the simple sugars produced by photosynthesis are used to make complex long chain and cross-linked molecules such as lignin that affects all species feeding on it Thus although these bonds can be broken at the temperatures experienced during combustion, what are the implications for biochemical reactions at the temperatures real organisms operate An intermediate position is provided by plant defense compounds where evolution is known to play a role and an evolved suite of herbivore species can detoxify those compounds, while the bulk of herbivore species cannot do so.

TABLE 1823 Treatment of Cyanide Poisoning

Combination of sodium nitrite and sodium thiosulfate is greater than the additive effects of both agents alone. 45 Sodium thiosulfate enhances the activity of the body's own detoxification enzyme, rhodanese, by acting as a sulfur donor. Rhodanese catalyzes the transfer of a sulfur molecule from thiosulfate to cyanide, forming thiocyanate, which is excreted by the kidneys. The rate of this detoxification reaction in humans is limited by the availability of sulfur. 4 There are limited data on the efficacy of sodium thiosulfate as sole therapy for cyanide poisoning in humans, although anecdotal reports suggest that it may be very effective as sole therapy. 21 This may be an important finding because sodium thiosulfate has very limited toxicity in comparison with nitrites and is a safer empirical therapy when the diagnosis is not clear. 8,18.

Udpglucuronosyltranferase 1a1

UDP-glucoronosyltransferases are enzymes responsible for detoxification and elimination of various metabolites and drugs. These enzymes also catalyze the inactivation of irinotecan (CPT-11), an analog of the alkaloid campto-thecin. CPT-11 is clinically used for the treatment of refractory and advanced colorectal cancers. Dose-limiting toxicities are diarrhea and pancytopenia. CPT-11 is metabolized to its active product, SN-38, by the enzyme carboxylesterase 2. As depicted in Fig. 3, UGT1A1 is responsible for the inactivation of SN-38, the most relevant metabolite of CPT-11, to the glucuronide of SN-38. CPT-11 can also be directly inactivated by formation of the inactive oxidation product, aminopenthan carboxylic acid (APC). Responsible for this step are cytochromes P450 3A4 and 3A5, as shown in Fig. 3. However, the formation of the SN-38 glucuronide is the

Examples of developments in plant GE

An alternative approach but still using A. tumefaciens has been to transfer the genes for mammalian cytochrome P450 monooxygenases, known to be involved in the detoxification (and activation) of many xenobiotics including pesticides, into tobacco plants. These transgenics displayed resistance to two herbicides, chlortoluron and chlorsulphuron (Yordanova, Gorinova and Atanassov 2001). Chapter 7 mentioned the genetic modification of a poplar to enable mercury to be removed from the soil and converted to a form able to be released to the atmosphere. This process is termed 'phytovolatilisation' (Rugh et al. 1998). The modification required a gene to be constructed, styled on the bacterial merA gene, by making a copy reflecting the codon bias found in plants using PCR technique. The mer A gene is one of a cluster of genes involved in bacterial detoxification of mercury, and is the one coding for the enzyme, mercuric ion reductase, which converts mercury from an ionic to a volatile form....

Conclusions And Questions To Address In Future Studies

Phytate might influence oxidative stress by mechanisms independent of its hydroxyl radical inhibiting characteristics. It may alter cell signaling pathways as proposed by Shamsuddin 1,22,23 , or it may influence the activity and expression of key enzymes in the antioxidant defense system. Singh and Singh 24 have reported that phytate given by oral gavage to lactating mice for 21 days led to increases in the activity of glutathione-S-transferase, (GST), the protein levels of cytochromes b5 and P-450, as well as the content of acid-soluble sulfhydryl groups in the livers of both the dams and their suckling pups. The GST family includes the non-selenium glutathione peroxidase, an important component of the cell's antioxidant defense machinery, and an enzyme that is upregulated in response to antioxidant nutrient deficiency 25 . Thus, phytate may also contribute to antioxidant defense by increasing the activity of key enzymes that detoxify ROS. Future research should also explore multiple...

Practical Toxicity Issues

In broad terms, type-A metals are less toxic than type-B, but this is only a generalisation and a number of other factors exert an influence in real-life situations. Passive uptake by plants is a two-stage process, beginning with an initial binding onto the cell wall followed by diffusion into the cell itself, along a concentration gradient. As a result, those cations which readily associate with particulates are accumulated more easily than those which do not. In addition, the presence of chelating ligands may affect the bio-availability and thus, the resultant toxicity of metals. Whereas some metal-organic complexes (Cu-EDTA for example) can detoxify certain metals, lipophilic organometallic complexes can increase uptake and thereby the functional toxic effect observed.

Other resistance approaches

Gene rapidly triggers a defensive response in the plant at the point of infection. A number of cells surrounding the infection site engage in the production of metabolites, toxins and other chemical and enzymatic defence substances to fight the pathogen, detoxify harmful excretions and contain the spread of the pathogen. This response leads to localised cell death and is known as the hypersensitive response (HR). Manipulation of the HR is one of the most promising new strategies to confer broad-spectrum resistance to agricultural crops. Ubiquitous expression of the R and the corresponding Avr genes simultaneously would result in the death of the plant but expression of the Avr gene under the control of a pathogen-activated promoter could theoretically lead to protection. The idea is that upon infection, pathogen elicitors would trigger the Avr gene and therefore a comprehensive set of cell defensive responses as well as the localised cell death. This method has already been proved...

Adult Liver Stem Cells

The liver is responsible for the intermediary metabolism of amino acids, lipids, and carbohydrates, the detoxification of xenobiotics, and the synthesis of serum proteins. In addition, the liver produces bile that is important for intestinal absorption of nutrients, as well as the elimination of cholesterol and copper. All of these functions are primarily executed by hepatocytes. The biochemical properties and pattern of gene expression are not uniform among all hepatocytes metabolic zonation describes the different properties of periportal (adjacent to the portal triad) and pericentral (adjacent to the central vein) hepatocytes. For example, periportal hepatocytes express urea cycle enzymes and convert ammonia to urea, whereas pericentral hepatocytes express glutamine synthase and utilize ammonia to generate glutamine.

Microbial Effects On Host Animals

Detoxification of food components or endogenous products Recovery of endogenous nitrogen The microbial end products of the hindgut fermentation include the short-chain fatty acids acetate, propionate, and butyrate, along with the gases methane, hydrogen, and carbon dioxide. In the young pig, the short-chain fatty acids can contribute up to 30 of the maintenance energy of the animal, while in the adult pig this may be even greater. Among other animals, large variations exist in the amount of energy derived from hindgut volatile fatty acids, with the dog and human being at the low end (< 5 ) and the horse at the high end (> 30 ). Although volatile fatty acids and vitamins synthesized in the hindgut benefit the animal, the microbes also impose a considerable burden to the animals in terms of replacement of epithelial cells, detoxification of microbial metabolites, and production of inflammatory and immunological cells. The benefits and negative effects of microbes in the hindgut are...

Natural Microbial Bioremediators

Jungle Jim Liberman Dies

Another environmental disaster being treated with natural bioremedi-ation is the pollution of the Hudson River in New York with polychlori-nated biphenyls (PCBs). General Electric Corporation deposited these compounds along a 40-mile stretch of the river between 1947 and 1977. PCBs were used to manufacture hydraulic fluids, capacitors, pigments, transformers, and electrical equipment. PCBs come in 209 different and interconverting forms, and the toxicity of a particular PCB depends upon the number of chlorine atoms it includes. Debate rages over whether it is better to remove and bury the most contaminated sediments, or to allow natural bacteria in the river to detoxify the PCBs. The bioremediation of the Hudson River is occurring in three stages. First, buried anaerobic bacteria strip off chlorines. In the water column, aerobic bacteria cleave the two organic rings of the PCBs. Finally, other microorganisms degrade the dechlorinated, broken rings into carbon dioxide, water, and...

Experimental Approach

Metallothioneins are possibly involved in detoxification processes in marine organisms occurring after exposure to heavy metals such as cadmium, zinc and copper (Bonham et al. 1987 Lyons-Alcantara et al. 1998 Cajaraville et al. 2000). Therefore, we also investigated the effects of exposure to sublethal concentrations of cadmium chloride on the expression of the metallothionein gene during the development of P. lividus sea urchin embryos (Russo et al. 2003). Northern blot analysis and RT-PCR experiments revealed that the metallothionein gene is constitutively expressed at low levels in control embryos at cleavage, swimming blastula, late gastrula and pluteus stages (6,12,24 and 48 h after fertilization Russo et al. 2003). The levels of metalloth-ionein transcripts increase with the developmental stage, in agreement with results reported by others (Wilkinson and Nemer 1987). However, when embryos were cultured in the presence of sublethal concentrations of cadmium chloride and harvested...

Distribution And Storage

The major sites of storage for toxins are (1) bound to plasma proteins, (2) the liver and kidneys, and (3) adipose tissue. Plasma proteins form complexes with many toxicants, serving to solubilize and transport them. The effect of protein binding depends on how the proteins compete with processes that detoxify or excrete them. If they give up the toxicants readily, they may help to transport them to the detoxification site. If, on the other hand, protein binding is relatively strong, it may sequester the toxins away from detoxification. Toxins are often concentrated in the liver or kidneys, possibly due to their role in detoxifying and excreting them. They contain their own binding proteins. An example is metallothionein, which figures in cadmium storage and in the transfer of cadmium from the liver to the kidney. Toxins absorbed in the stomach and intestines must pass through the liver before reaching other parts of the body, thus giving that organ a chance

Other Factors Encouraging a Competitive Health Care Market

The first time outpatient surgery, outpatient detoxification, partial hospitalization, and a number of other alternatives to costly hospitalization became part of the benefit package. Manufacturing had become increasingly concerned with how many dollars health insurance was adding to each unit of production. This was of particular concern to the automotive industry that had become engaged in fierce competition with Japanese car manufacturers. The addition on the average of 800 in health insurance premiums to the cost of every automobile placed American carmakers at a disadvantage. This was only the first of a number of steps taken by American business, not the least of which was the formation around the country of business groups on health that educated business leaders and pressured the health care sector for financial accountability.

Why are cats prone to certain toxicoses

However, one of the major factors responsible for the susceptibility of felines to various toxic compounds relates directly to their limited ability to metabolise and detoxify such compounds, particularly compared with other species such as the dog. The list of agents affected by this phenomenon includes many commonly used veterinary medicinal products, household chemicals

Biochemistry and Metabolic Functions

The other reaction is the transmethy-lation of homocysteine by 5-methyl-tetrahydrofolate to methionine, catalyzed by the enzyme methionine synthase (N5-methyltetrahydrofolate homocysteine methyltransferase) which requires methylcobalamin as coenzyme and is located in the cytosol. It is through their essential roles in this important metabolic reaction that cobalamin and folate interact and are linked with respect to their importance in nutrition. In addition, there are major similarities in the effects of their deficiencies in humans. These will be discussed below. Considering this 'metabolic crossroad' for the two vitamins, it may be pointed out that without adequate supplies of both nutrients, the synthesis of methionine and its derivative S-adenosyl-methionine (SAM) is disrupted, with consequent profound effects on normal cellular function. Methionine is a key and essential amino acid and normal supply depends critically on recycling through the remethy-lation...

Integrating Genetic and Environmental Information in Clinical Research

The EGP will develop in several stages. In the first phase of the project, experts will identify a set of approximately 500 genes that appear to play a role in the development of environmentally-induced diseases. These will include xenobiotic metabolism and detoxification genes, DNA repair genes, signal transduction genes, and genes involved in oxidative processes. Having identified a set of genes that appear to be involved in environmental response, the second phase of the project will catalogue common genetic differences in these genes differences that may affect the functioning of the associated enzymes. Finally, in the third phase of the EGP, researchers will study the biological implications of these genetic differences using functional assays and population-based studies of gene-environment interactions. Organizers of the project expect that the first two phases of the EGP will be completed in late 2004. The third phase of the project will require significantly more time to...

GlutathionesTransferases

The glutathione-S-transferases (GST) are important phase II detoxification enzymes found mainly in the cytosol, and are involved in the detoxification of drugs and harmful chemicals in the body (112). They are found in very high concentrations in the liver, where they conjugate glutathione to the electrophilic centers of lipophilic compounds and increase their solubility in order to facilitate their excretion (113,114) (Figure 10.7). GST posses a wide range of substrate specificities and can catalyze the reduction of breakdown products of macromolecules formed as a result of oxidative stress including reactive unsaturated carbonyls, oxidized DNA bases, and hydroperoxides, and therefore play a vital role in protecting tissues against oxidative damage and oxidative stress (112-115). As a result of the beneficial functions of GST it serves as an important biomarker for oxidative stress (115). Most of the methods to assay the GST activity involve measuring the conjugation of...

Mechanisms of Carcinogenicity

The direct metabolic activation of compounds to carcinogenic species by phase II metabolism, a process normally associated with detoxification, can also occur. Thus safrole and related compounds are converted to their sulfate esters, the ultimate carcinogenic species by the phase II enzyme, sulfotransferase.

Current limitations of the heterologous expression system

Although heterologous expression and calcium imaging has proven to be a powerful tool to elucidate the functional properties of individual taste receptors, this system has some limitations and does not fully mimic the human tongue. On the tongue, the taste receptor cells are embedded in taste buds and present only a restricted part of their surface to the tastants (McCaughey and Scott 1998). In addition, taste receptor cells express transporters that contribute to the detoxification of compounds (Jakob et al. 1998). This helps to protect the cells in their native environment from osmotic pressure as well as toxic effects elicited by some tastants. In the in vitro expression system bath application is used and, therefore, the whole surface of the transfected cells is exposed to the tastant (Chandrashekar et al. 2000, Bufe et al. 2002, Li et al. 2002). The use of some tastants in the heterologous system can therefore be problematic, or even impossible, because the cells might show...

Herbicide Resistant Crops

Bioremediation is the use of organisms to break down and thereby detoxify dangerous chemicals in the environment. Plants and microorganisms are used as bioremediators. The technology can take advantage of a natural metabolic pathway or genetically modify an organism to have a particular toxic appetite.

Nuclear Receptors As Transcriptional Regulators Of Bile Acid Homeostasis

Receptor that typically utilizes drugs and xenobiotics as its ligands.66 In response to these ligands, PXR induces the expression of genes encoding proteins involved in drug detoxification and elimination pathways. In addition to xenobiotics, certain bile acids, such as the highly toxic LCA, can serve as agonistic ligands for PXR.67-68 Indeed, activation of PXR can protect mouse livers against LCA-mediated injury.67 Doubleknockout mice lacking both FXR and PXR exhibit more severe disturbances of bile acid metabolism than mice lacking only one of the nuclear receptors, demonstrating that both contribute to bile acid homeostasis.69 PXR is a master regulator of the gene encoding the CYP3A4 enzyme,70 which, in addition to its role in detoxifying xeno-biotics, also metabolizes bile acids to less toxic and more easily excreted derivatives. Thus, by being both activators of the CYP3A4 gene and substrates of the CYP3A4 enzyme, bile acids can initiate a hepatoprotective feedforward loop via...

Carcinogenesis

Another type of epigenetic carcinogen is the cocarcinogens These increase the concentration of an initiator by affecting absorption, biotransformation, or detoxification. For example, they may decrease detoxification by inhibiting enzymes or depleting detoxification substrates such as glutathione. Ferric oxide and asbestos may facilitate cellular uptake of genotoxics.

Oxygen toxicity

High concentrations of oxygen over long periods are known to cause lung damage. In hyperoxia, cellular production of oxygen free radicals exceeds the capacity of antioxidant enzymes to detoxify them. These free radicals cause alveolar cell and microvascular injury. Early toxicity is almost completely reversible. Later, organization occurs, with interstitial fibrosis. Retrosternal pain, presumably from tracheal inflammation, appears to be an early indicator

Aflatoxin

Aflatoxins are heat stable and easily transformed to toxic products. Treatment with ammonia reduces and inactivates aflatoxins. Lactic fermentation at pH < 4.0 results in the conversion of AFB1 to AFB2a, which is less toxic. Other environmental conditions, such as the presence of organic acid, also irreversibly convert AFB1 to aflatoxicol B, which is 18 times less toxic than AFB1. Detoxification results in the opening of the lactone ring (see Figure 13.2) and can be monitored by reduced fluorescence.

Nitrogen Metabolism

The dam also must dispose of the significant increase in products of nitrogen catabolism generated by conceptus tissues during late pregnancy. Fetal urea synthesis is substantial because of extensive oxidative deamination of amino acids in fetal liver and other tissues. This urea is efficiently transported by the placenta to the maternal circulation and adds directly to maternal urea destined for renal clearance and excretion. The placenta, which has little urea cycle enzyme activity, also deaminates amino acids to an extent that causes perceptible increases in maternal blood-ammonia concentrations and the need for hepatic detoxification. 3

Superoxide Dismutase

Catalase (EC 1.11.1.6) is a ubiquitous oxidoreductase that is present in most aerobic cells. Catalase (CAT) is involved in the detoxification of hydrogen peroxide (H2O2), a (ROS), into molecular oxygen and two molecules of water (22,23). CAT can be assayed directly by measuring the rate of appearance of molecular oxygen using a Clark-type electrode (124). Here, the enzyme extract is allowed to react with a known concentration of hydrogen peroxide. The formation of oxygen changes the potential of the Clark-type electrode which is proportional to the enzyme activity (124). Catalase activity has also been determined spectrophotometrically at 240 nm by monitoring the disappearance of hydrogen peroxide at pH 7.0 (125). Catalase also has a peroxidative activity which has been used to assay its activity by reaction with methanol in the presence of an optimal concentration of H2O2 (126,127). The formaldehyde produced is measured spectrophotometrically with (Purpald) as the chromogen, in which...

Pathophysiology

Cellular detoxification, a property apparently not shared by MRP6, and has a capacity to confer chemotherapy resistance to the cells. While the exact pathomechanisms leading to abnormalities in the elastic fiber network of the target organs are poorly understood, deposition of calcium is considered merely a secondary change that can occur after trauma to elastic fibers. As a result of calcification, fragmentation or disorganization of elastic fibers in the midreticular dermis and the medium-sized arteries and veins as well as the fractures in Bruch's membrane behind the retina occurs. In the skin, this leads to inelasticity, loss of recoil, and subsequent sagging of the skin. In the eye, neovascularization occurs at sites of fracture due to calcium deposits. These newly formed vessels are fragile and often rupture with trauma. In the arteries, alteration of elastic fibers leads to calcification of the elastic media and later the intima, which facilitates atherosclerotic peripheral...

The Liver

The liver is the largest solid organ in the body, constituting 2 to 5 of the body weight in adults and is considered to be of major importance in the body's defense mechanism against bacteria and foreign macromolecules derived from bacteria and microorganisms (51). The liver consists of various cell types liver parenchymal cells (hepatocytes), endothelial cells, and Kupffer cells. The liver parenchymal cells represent 60 of the liver cells. Liver parenchymal cells are main producers of plasma proteins (e.g., albumin) and acute-phase proteins. Liver endothelial cells exhibit several receptors that allow endocytosis of (foreign) ligands such as LPS and LTA (52). Kupffer cells are the liver macrophages, which constitute 805 to 90 of the fixed tissue macrophages reticuloendothelial system (RES) . Kupffer cells remove all kinds of old, unnecessary and damaged material from the circulation (immune complexes, erythrocytes, tumor cells, cellular debris, and apoptotic cells) (52). In addition,...

Abcc1

Some studies suggested an involvement of Abccl in the efflux of substances from the brain into blood,184 whereas others did not.185'186 In human and murine kidney, ABCCl Abccl is present in the epithelial cells of the loop of Henle and urinary collecting ducts.176'187 In colon, highest ABCC1 levels are found in the Paneth cells of the crypts, but not in the epithelial cells.187 This ABCC1 tissue distribution and localization pattern, which is almost mutually exclusive to that of ABCC2 (Section 11.5.2), indicates that ABCC1 has an important function in the detoxification of substances from those cells and tissues that do not express ABCC2. Subsequent to its first demonstration in the canalicular membrane of rat and human hepatocytes,8'41'156 ABCC2 Abcc2 was also identified in the apical membrane of polarized cells of rat and human kidney proximal tubules,188'189 human small intestine,190'191 colon,141'191 gallbladder,192 bronchi,141'191 and placenta.180'193 The exclusive apical...

Ornithine Cycle

Ornithine Cycle

The ornithine cycle, also known as the urea cycle and the Krebs-Henseleit cycle, is the pathway in mammalian liver that allows the detoxification and excretion of excess nitrogen as urea. Flux through the cycle is driven by the demand to remove excess ammonia derived from the degradation of amino acids that arise either from the diet or from endogenous proteolysis. In a healthy individual, consuming a typical western diet, flux through the ornithine cycle produces some 30-35 g of urea per day but as much as 25 of this can be recycled via hydrolysis to ammonia and bicarbonate by colonic bacteria. The function of the ornithine cycle is to detoxify excess ammonia in the mammalian body and as such the source of the ammonia must be considered whenever the cycle is discussed in more than simple chemical terms. There are two types of condition when the delivery of ammonia within the liver is high and thus require high rates of urea synthesis. The first is in response to dietary (exogenous)...

Dpd Inhibitors

While the three others act as DPD inhibitors (competitive inhibition). Details on the clinical development on these compounds will be given in other chapters in this book. We will insist on the main characteristics of these DPD inhibitors. With 5-ethynyluracil pretreatment, the biovailability of 5-FU becomes complete and thus renal clearance becomes the main source of drug elimination with significant correlations having been shown between 5-FU clearance and creatinine clearance (35). A consequence could be that dosage reductions would need to be made in patients with reduced renal function who are candidates for 5-ethynyluracil and 5-FU combined treatment. Competitive inhibitors of DPD activity are also part of the new products UFT, Si, and BOF-A2. UFT contains uracil and tegafur in a 4 1 ratio and Si includes 5-chloro-2,4-dihydropyrimidine (CDHP) in combination with tegafur and potassium oxonate. BOF-A2 is an oral prodrug of 5-FU and 3-cyano-2,6-dihydropyrimidine (CNDP). CNDP is a...

Nat And Disease

Because of the role of acetylation in the metabolic activation and detoxification of arylamine and heterocy-clic carcinogens, acetylator status and cancer risk have been widely investigated. Unlike the relatively rare but highly penetrant genes involved in familial cancers, those genes responsible for metabolic polymorphisms have low penetrance and cause only a moderate increase in cancer risk. Nevertheless, their widespread occurrence in the general population suggests they are a significant contributor to individual risk. However, few diseases have consistently demonstrated a relationship between pheno-type and risk. For example, several studies have implicated the rapid phenotype as an increased risk factor for colon cancer, 15-17 whereas others have been unable to confirm this finding. 18-20 Geographical differences, ethnicity, lack of study power, dietary differences, and differences in other risk factors between study groups have been suggested as reasons for variable results...

KXH kXH HCHO

Endogenous Sulfate Metabolism

Methyl groups are transferred from one of two methyl donor substrates, S-adenosyl-methione (SAM) or A5-methyltetrahydrofolic acid. Methylation occurs with a variety of methyl-acceptor substrates, including proteins, nucleic acids, and phospholipids. Interestingly, methyl conjugates are generally less water soluble than the parent compound. However, methylation is generally considered a detoxification reaction. Processes that produce a one-electron reduction of oxygen produce a more reactive radical, the superoxide anion. The superoxide anion can be formed from oxygen by an enzyme in white blood cells and other enzymes or certain toxic agents. ROS can be eliminated by the enzymes superoxide dismutases, which convert two molecules of superoxide to one molecule each of hydrogen peroxide and oxygen (Figure 9.9). Hydrogen peroxide is another ROS that can be formed by some two-electron transfer reactions. As illustrated in Figure 9.9, hydrogen peroxide is detoxified by glutathione...