The PON1 gene and detoxication

It has been assumed since its discovery that serum paraoxonase (PON1) plays a major role in the detoxication of specific organophosphorus compounds. I t was also assumed that individuals with low PON1 activity would be more su sceptible to paraoxon/parathion poisoning than individuals with higher PON7 activity. Evidence supporting this hypothesis was provided by injection of rabbit PON7 into rodents. Injected PON7 protected against paraoxon toxicit y in rats and chlorpyrifos oxon toxicity in mice. The recent availability o f PON1 knockout mice has provided an in vivo system with which one can more closely examine the role of PON1 in detoxication. PON7 knockout mice demon strated dramatically increased sensitivity to chlorpyrifos oxon and diazoxo n and moderately increased sensitivity to the respective parent compounds. The PON1 knockout mutation also resulted in the elimination of liver PON1 a ctivity accounting for the dramatic increase in sensitivity to chlorpyrifos oxon and diazoxon. Totally unexpected was our finding that the PON7 knocko ut mice were not more sensitive to paraoxon. This was particularly surprisi ng in light of the earlier enzyme injection experiments. Differences in the relative catalytic efficiencies of rabbit vs, mouse PON1 for the specific oxon forms explain these observations. Mouse PON1 has good catalytic effici ency for the hydrolysis of diazoxon and chlorpyrifos oxon, but a poor effic iency for paraoxon hydrolysis relative to rabbit PON1. The human PON1Q192 i soform has a catalytic efficiency similar to that of mice, whereas the huma n PON1R192 isoform has a much better catalytic efficiency, predicting that individuals expressing high levels of the PON1R192 isoform may have increas ed resistance to paraoxon toxicity. (C) 2000 Inter Press, Inc.