Genetic Polymorphism in Paraoxonase 1 (PON1): Population Distribution of PON1 Activity

摘要: Paraoxonase-1 (PON1) is a serum esterase that hydrolyzes the activated oxon form of several organophosphates. The central role PON1 in detoxification organophosphate (OP) pesticides was demonstrated knockout mouse studies, suggesting human variability needs to be considered health risk assessments involving exposure these pesticides. current analysis focused on two genetic loci which polymorphisms affect activity. Detailed kinetic studies and population found *192Q (wild type) allele more active toward some substrates (such as sarin, soman, diazoxon) less others paraoxon or chlorpyrifos) relative variant *192R allele. Another affects activity *55M; enzyme quantity, rather than specific substrate preference, altered. occurs commonly with frequency 25-64% across populations analyzed. *55M common, occurring 5-40% individuals depending upon ethnic group studied. These data were incorporated into Monte Carlo simulations both alleles simultaneously modeled Caucasian, African American, Japanese populations. resulting distributions bimodal for approximately fourfold differences between low- high-activity modal medians. Differences total median 1st percentile five- sixfold. When sarin metabolic simulated, unimodal. However, there an even greater degree interindividual (median difference >20-fold). results show combined effects allelic variants yielded distribution associated considerable This indicates need evaluate polymorphism-related display internal doses adverse responses. may best achieved via physiologically based pharmacokinetic (PBPK) models input distributions, such those generated this analysis, simulate range possible population.