Polymorphism Of The P450 Genes

Today, we know about 57 active cytochrome P450 genes (http://drnelson.utmem.edu/CytochromeP450.html, Ref. [7]). All P450 genes in families 1-3 are polymorphic. The functional importance of the variant alleles is, however, different and the frequencies of their distribution in different ethnic groups are tremendously different. On the Human CYPallele Nomenclature Web site at our server at Karolinska Institutet (http://www.imm.ki.se/cypalleles), updated information in this area is obtained. About 40% of P450-mediated drug metabolism is carried out by polymorphic enzymes. The rate of hepatic metabolism of a certain drug can differ 1000-fold between the phenotypes. Particularly high penetrance of the genetic polymorphism is seen because of variation in the CYP2C9, CYP2C19, and CYP2D6 genes. CYP2D6 is responsible for the metabolism of about 25% of the clinically used drugs, and the polymorphism is relevant for interindividual variability in about 50% of these drugs, i.e., of about 10-15% of all drugs used today (cf. Ref. [8]). Required dosing to achieve the same plasma levels of a drug mainly metabolized by CYP2D6 can differ 10-20-fold between individuals. In Europe, 5.5% of the population are UMs for CYP2D6, and here, no response is often to be expected because of too rapid metabolism. Seven percent of the European population are PMs, where too high plasma levels of the drugs are to be expected at ordinary dosage and a higher frequency of adverse drug reactions is seen. In contrast to the extensive span in metabolic capacity, dosing today is, however, principally only based on the average in the population. By predictive genotyping, a more appropriate initial dosing could be achieved in 50-60 million people only within Western Europe.

About 50% of all drug metabolism in phase I is carried out by CYP3A4. This enzyme is highly conserved and no functionally important variant forms are seen in Caucasians or Orientals. There is a relatively high interindividual variability in CYP3A4 activity, but any genetic origin has to be addressed in future studies.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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