Genetic and temporal determinants of pesticide sensitivity: Role of paraoxonase (PON1)

Susceptibility to organophosphorus (OP) insecticides and nerve agents is st rongly influenced by genetic and developmental factors. A number of organop hosphorothioate insecticides are detoxified in part via a two-step pathway involving bioactivation of the parent compound by the cytochrome P450 syste ms, then hydrolysis of the resulting oxygenated metabolite (oxon) by serum and liver paraoxonases (PON1). Serum PON1 has been shown to be polymorphic in human populations. The Arg(192) isoform (PON1(R192)) of this HDL-associa ted protein hydrolyzes paraoxon (POX) at a high rate, while the Gin,, isofo rm (PON1(Q192)) hydrolyzes paraoxon at a low rate. The effect of the polymo rphism is reversed for the hydrolysis of diazoxon (DZO) soman and particula rly sarin. Phenylacetate is hydrolyzed at approximately the same rate by bo th PON1 isoforms and chlorpyrifos oxon (CPO) slightly faster by the PON1R(1 92) isoform. In addition to the effect of the amino acid substitution on ra ces of toxicant hydrolysis, two other factors influence these rates. The ex pression of PON1 is developmentally regulated. Newborns have very low level s of PON1. Adult levels in rats and mice are reached at 3 weeks of age and in humans, sometime after 6 months of age. In addition, among individuals o f a given genotype, there is at least a 13-fold difference in expression of PON1 that is stable over time. Dose/response experiments with normal mice injected with purified PON1 and with PON1 knockout mice have-clearly demons trated that the observed differences of in vitro rates of hydrolysis are si gnificant in determining differential sensitivities to specific insecticide s processed through the P450/PON1 pathway. Injection of purified rabbit PON 1 protects mice from cholinesterase inhibition by chlorpyrifos (CPS) and CP O. Knockout mice are much more sensitive to CPO and DZO than are their PON1 +/+ littermates or wild-type mice. A number of recent reports have also ind icated that the PON1R(192) isoform may be a risk factor for cardiovascular disease. Studies with PON1 knockout mice are also consistent with a role of PON1 in preventing vascular disease. (C) 2000 Inter Press, Inc.