Paraoxonase 1 (PON1) Status in Risk Assessment for Organophosphate Exposure and Pharmacokinetics

Abstract

The use of enzymatic rate constants for physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling requires that the rate constants are physiologically relevant. To illustrate some of the approaches used to establish the validity and physiologically significance of in vitro determined rate constants, we have made use of data for the human high density lipoprotein (HDL)-associated enzyme paraoxonase 1 (PON1) and a mouse model system in which the PON1 protein levels and catalytic efficiency are genetically variable. A glutamine (Q)/arginine (R) polymorphism at amino acid position 192 of PON1 (Q192R) determines the catalytic efficiency of hydrolysis of some substrates with the PON1R192 alloform, for example, hydrolyzing chlorpyrifos oxon (CPO) more efficiently than the PON1Q192 alloform and protecting better against CPO exposure. The PON1-Q192R alloforms have equivalent catalytic efficiencies of diazoxon (DZO) hydrolysis and protect equally well against DZO exposure. The catalytic efficiency for paraoxon (PO) hydrolysis is too low to effectively protect against PO exposure. Epidemiological studies on human populations have shown that low PON1 levels are also a risk factor for vascular disease. Km values for substrate hydrolysis are presented as well as tables for interconverting rates of hydrolysis of different substrates to allow modeling of in vivo rates of OP substrate hydrolysis at different in vivo levels of OP when rates of hydrolysis of a non-toxic substrate such as phenyl acetate are measured in vitro. Establishment of correlation plots for drug metabolism will allow for the conversion of difficult assays to convenient high-throughput assays.