SERUM PARAOXONASE STATUS - A MAJOR FACTOR IN DETERMINING RESISTANCE TO ORGANOPHOSPHATES

A number of lines of evidence suggest that serum paraoxonase is protec tive against poisoning by organophosphorus substrates of this enzyme. Birds that have very low levels of paraoxon hydrolyzing activity in th eir sera are very susceptible to parathion poisoning. Rabbits, which h ave a sevenfold higher enzyme level compared with rats, have a fourfol d higher resistance to paraoxon poisoning than rats. Rabbit paraoxonas e hydrolyzes chlorpyrifos-oxon with a much higher turnover number than does rat paraoxonase, resulting in a very high resistance of rabbits to chlorpyrifos toxicity. Direct tests of paraoxonase protection have been carried out by injecting purified rabbit enzyme into rats. The pr otection achieved was higher for chlorpyrifos-oxon than for paraoxon, probably due to the high hydrolytic activity of the rabbit enzyme for chlorpyrifos-oxon. In humans, a substrate-dependent polymorphism of se rum paraoxonase is observed, where one isoform of paraoxonase has a hi gh turnover number for paraoxon and the other a low turnover number. B oth isoforms appear to hydrolyze chlorpyrifos-oxon and phenylacetate a t the same rate. Cloning and sequencing of the human paraoxonase cDNAs has elucidated the molecular basis of the polymorphism. Arginine at p osition 192 determines high paraoxonase activity, and glutamine at thi s position, low paraoxonase activity. In addition to the polymorphism, a 13-fold variation in serum enzyme levels within a given genetic cla ss is seen. The experiments reported here demonstrate that rabbit para oxonase injected into mice provides protection against the parent inse cticide chlorpyrifos as well as the toxic oxon. These results suggest that serum paraoxonase status may serve as a biomarker for insecticide susceptibility in humans.