Received for publication October 4, 2006.
Revised November 16, 2006.
Accepted for publication November 16, 2006.

The relationship between PON1 phenotype and PON1-192 genotype in detoxification of three oxons by human liver

Abstract

Abstract Phosphorothioate pesticides (OPs) such as diazinon, chlorpyrifos and parathion are activated to highly toxic oxon metabolites by the cytochromes P450 (CYPs), mainly in the liver. Simultaneously, the P450s catalyse detoxification of OPs to non-toxic dearylated metabolites. The oxon is then detoxified to the dearylated metabolite by PON1, an A-esterase present in the liver and blood serum. The aims of this study were to define the influence of PON1-192 genotype and phenotype on the capacity of human liver microsomes (n=27) to detoxify the oxons diazoxon, chlorpyrifos-oxon and paraoxon. Near physiological assay conditions were used to reflect as closely as possible metabolism in vivo and because the hydrolytic activity of the allelic variants of PON1-192 are differentially affected by a number of conditions. The rates of hydrolysis of diazoxon, chlorpyrifos-oxon and paraoxon varied 5.7-fold, 16-fold and 56-fold, respectively, regardless of PON1-192 genotype. Individuals with the PON1-192RR genotype preferentially hydrolysed paraoxon (p<0.01) and the R allele was associated with higher hydrolytic activity towards chlorpyrifos-oxon, but not diazoxon. There were strongly significant relationships between phenylacetate and paraoxon hydrolysis (p<0.001), and phenylacetate and chlorpyrifos-oxon hydrolysis (p<0.001), but not between phenylacetate and diazoxon hydrolysis. These data highlight the importance of PON1 phenotype for efficient hydrolysis of paraoxon and chlorpyrifos-oxon, but environmental and yet unknown genetic factors are more important than PON1-192 genotype in determining capacity to hydrolyse diazoxon.

Key words: human genetics, insecticides, liver microsomes, pharmacogenetics, toxicology