Role Of Pon1 In Organophosphate Toxicity

Several in vitro experiments have shown that PON1 hydrolyzes a number of organophosphates—among these, paraoxon, chlorpyrifos oxon, and diazoxon; active metabolites of the insecticides parathion, chlorpyrifos, and diazinon; as well as nerve agents sarin, soman, and VX. The effects of the PON1192 polymorphism may be substrate-dependent, as the PON1q192 isoform hydrolyzes diazoxon, sarin, and soman more rapidly than PON1R192

Fig. 2 Determination of PON1 Status. Plot of diazoxonase vs. paraoxonase activities in the plasma of carotid artery disease cases and controls, coded for PON1 Q192R genotype (determined by PCR). Note that the two-substrate assay provides an accurate inference of PON1192 genotype as well as the level of plasma PON1 activities (PON1 status). Because it is a functional analysis, it provides a 100% accurate determination of the functional genomics of PON1 status. Newly discovered SNPs explain why some individuals have lower PON1 activity than would be predicted by Q192R genotype alone. Individuals 1-4 were genotyped as heterozygotes (Q/R192); however, their enzyme analysis indicated homozygosity for Q or R. Complete sequencing of their PON1 genes revealed mutations in one allele, resulting in only one alloform of PON1 in their serum. The mutations revealed are noted in the figure. (Note the large variability in PON1 levels, even among individuals of the same Q192R genotype). (From Refs. [7], [9], and [15].)

Fig. 2 Determination of PON1 Status. Plot of diazoxonase vs. paraoxonase activities in the plasma of carotid artery disease cases and controls, coded for PON1 Q192R genotype (determined by PCR). Note that the two-substrate assay provides an accurate inference of PON1192 genotype as well as the level of plasma PON1 activities (PON1 status). Because it is a functional analysis, it provides a 100% accurate determination of the functional genomics of PON1 status. Newly discovered SNPs explain why some individuals have lower PON1 activity than would be predicted by Q192R genotype alone. Individuals 1-4 were genotyped as heterozygotes (Q/R192); however, their enzyme analysis indicated homozygosity for Q or R. Complete sequencing of their PON1 genes revealed mutations in one allele, resulting in only one alloform of PON1 in their serum. The mutations revealed are noted in the figure. (Note the large variability in PON1 levels, even among individuals of the same Q192R genotype). (From Refs. [7], [9], and [15].)

in in vitro assays.[5] However, PON1R192 is more efficient at hydrolyzing paraoxon and chlorpyrifos oxon than the Q isoform. The existence of polymorphisms in PON1 that confer different hydrolyzing abilities toward OPs, as well as different levels of expression, has long suggested that certain individuals may be more sensitive to OP toxicity.

Animal studies have provided evidence for the role of PON1 in modulating OP toxicity, and have clarified the role of PON1192 polymorphism. Initial studies showed that administration of exogenous PON1 to rats or mice would confer protection against the acute toxicity of various OPs (reviewed in Refs. [11] and [16]). Further evidence was provided by studies carried out in PON knockout (PON1~/ ") mice and PON1 transgenic (TG) mice expressing either the human PON1R192 or the PON1q192 allele. As predicted, PON1~/ " mice have drastically increased sensitivity to the toxicity of chlor-pyrifos oxon and diazoxon, but not to paraoxon.[17,18] Administration of purified human PON1R192 or PON1q192 to PON1~/ _ mice indicated that both isoforms were equally protective toward diazoxon toxicity and equally ineffective in protecting against paraoxon toxicity, whereas PON1R192 offered better protection than the PON1q192 isozyme toward chlorpyrifos oxon.[18] These in vivo findings were explained by results from kinetic analyses of substrate hydrolysis by purified human PON1 isoforms under physiological conditions. The catalytic efficiencies of both isoforms for diazoxon were similar, whereas that of PON1R192 was higher than PON1q192 for chlorpyrifos oxon. In case of paraoxon, even though the PON1 R192 was more efficient than PON1q192, its overall catalytic efficiency was very low, indicating that PON1 does not play a significant role in detoxifying paraoxon in vivo.[18] Studies in TG mice have supported these findings by indicating that the toxicity of chlorpyrifos oxon is greatly reduced in hPON1R192 TG mice, but not in hPON1Q192 TG mice compared with PON1~/" mice.[19] Current work is exploring the role of PON1 in modulating the effects of OPs on gene expression in the brain by microarray analysis. Although these studies clearly indicate that the PON1192 genotype and the level of PON1 expression modulate OP toxicity in animal models, direct confirmation in humans of the relevance of PON1 status in determining relative sensitivity to OP toxicity needs to be further investigated. The limited number of studies aimed at testing this hypothesis in humans has been recently summarized,[16] but more studies are needed, where better indications of the level and nature of exposure and the consequences of exposure are documented. Nevertheless, results of animal studies have also pointed out the potential therapeutic use of PON1 in treating individuals for exposure to OP insecticides or nerve agents. Engineering recombinant PON1 variants with high catalytic efficiencies toward specific compounds may indeed prove to be a useful addition to the treatment of OP intoxication.[10]

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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