Pharmacogenomic considerations of the paraoxonase polymorphisms

Abstract

The high density lipoprotein (HDL)-associated enzyme paraoxonase-1 (PON1) exhibits a substrate-dependent activity polymorphism as well as a large variability in plasma levels among individuals. The PON1 activity polymorphism is determined mainly by a glutamine(Q)/arginine(R) substitution at position 192 of PON1 (PON1Q192R). There is one additional polymorphism in the coding region at L55M, five in the 5′ regulatory region and four in the 3’ untranslated region. One of the five promoter polymorphisms (C-108T) appears to have a major effect on the levels of PON1 found in plasma. Two factors are important to consider in evaluating the pharmacogenetics of PON1 in an individual, the amino acid present at position 192 and the level of their plasma PON1. ‘PON1 status’, measured easily via a two-substrate assay, provides data for both of these critical factors. As such, PON1 status will be more useful than genotyping alone for identifying individuals at risk for cardiovascular disease, for predicting sensitivity to OP insecticides, and possibly nerve agents, for predicting the disposition of drugs known to be activated or hydrolyzed by PON1 and for developing robust pharmacokinetic models for each of these roles of these roles of PON1.