Understanding the significance of genetic variability in the human PON1 gene

A major goal of the environmental genome project has been to understand human genetic variability as it affects sensitivity or resistance to different environmental exposures. The human PON1 gene was one of the early-identified genes whose polymorphisms affected both the detoxication of xenobiotics and metabolism of important physiological substrates. PON1 encodes an HDL-associated enzyme that hydrolyzes a number of aromatic esters, organophosphorus (OP) compounds, drugs and oxidized lipid molecules. Our early studies demonstrated that of the two common coding region polymorphisms L55M and Q192R, it was the latter that affected the catalytic efficiency of hydrolysis of toxic organophosphorus (OP) insecticide metabolites. PON1(R192) hydrolyzes paraoxon and chlorpyrifos oxon with better catalytic efficiency than PON1(Q192) but soman and sarin with lower efficiency. Both 192 isoforms hydrolyze diazoxon and phenylacetate with approximately the same catalytic efficiency. While large differences in catalytic efficiency are observed for some substrates, the catalytic efficiency must reach a certain value to provide in vivo protection against OP exposures. In addition to the coding region polymorphisms that affect catalytic efficiency of substrate hydrolysis, polymorphisms that affect PON1 expression have been characterized in the 5' regulatory region of PON1. Experiments with PON1 knockout mice, PON1 injected knockout mice and transgenic mice expressing only human PON1(R192) or PON1(Q192) have provided important insights into the effects of both coding region and regulatory region polymorphisms on the modulation of OP exposures by the human plasma PON1 isoforms.