Human paraoxonase 1 hydrolysis of nanomolar chlorpyrifos-oxon concentrations is unaffected by phenotype or Q192R genotype

Abstract

The organophosphorus insecticide chlorpyrifos has been widely used. Its active metabolite chlorpyrifos-oxon (CPO) is a potent anticholinesterase and is detoxified by paraoxonase-1 (PON1). PON1 activity is influenced by numerous factors including a Q192R polymorphism. Using forty human blood samples bearing homozygous genotypes and either high or low activity phenotypes (as determined by high concentration assays of paraoxon and diazoxon hydrolysis) the serum PON1 hydrolysis of high (320 μM) and low (178 nM) CPO concentrations was assessed using direct or indirect spectrophotometric methods, respectively. PON1 activity at high CPO concentration reflected the phenotype and genotype differences; subjects with the high activity phenotype and homozygous for the PON1R192 alloform hydrolyzed significantly more CPO than subjects with the low activity phenotype and/or PON1Q192 alloform (High RR=11023±722, Low RR=9467±798, High QQ=8809±672, Low QQ=6030±1015 μmoles CPO hydrolyzed/min/L serum). However, PON1 hydrolysis of CPO at the lower, more environmentally relevant concentration showed no significant differences between the PON1192 genotypes and/or between high and low activity phenotypes (High RR=231±27, Low RR=219±52, High QQ=193±59, Low QQ=185±43 nmoles CPO/min/L serum). Low CPO concentrations were probably not saturating, so PON1 did not display maximal velocity and the PON1 genotype/phenotype might not influence the extent of metabolism at environmental exposures.

Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk—an exploratory study

“…However, the mechanism is unclear and does not seem to be related to the hydrolysis efficiency, since R-carriers have higher paraoxonase activity than QQ homozygotes. Besides, at relatively low exposure levels, as in this study, the capacity to detoxify organophosphates is considered to be independent of the PON1 Q192R genotype [114], and furthermore, serum PON1 activity was reported to be low in newborns and may be even lower before birth, as indicated by lower activity in premature compared to term babies [115, 116]. Thus, differences in fetal detoxification of pesticides related to PON1 genotype might not be a likely explanation of the exposure-related difference in methylation pattern between children with the QR/RR and QQ genotype.…”

Reproductive Health Risks Associated with Occupational and Environmental Exposure to Pesticides

“…However, for diazoxon (the active oxon-metabolite of diazinon), R-carriers have a higher catalytic rate, explaining their higher susceptibility towards high diazinone exposure among sheep dippers carrying the R-allele [117]. At lower exposure levels, the capacity to detoxify organophosphates is considered to be independent of the PON1 Q192 genotype [118]. Thus, the higher susceptibility among R192-carriers reported in some of the studies above seems unrelated to the hydrolysis efficiency of the enzyme.…”

Human paraoxonase-1 (PON1): Gene structure and expression, promiscuous activities and multiple physiological roles

“…Therefore, the majority of studies in this area have concentrated on PON1 as a genetic determinant of OP toxicity [103]. Recently, however, studies have indicated that at environmentally relevant concentrations (nanomolar) of CPoxon, it is unlikely that PON1 genotypes would influence an individual's ability to hydrolyse CPoxon [105]. …”