Determination of paraoxonase (PON1) status requires more than genotyping

Human serum paraoxonase (PON1) is associated with high density lipoprotein (HDL) particles. This enzyme is involved in the metabolism of oxidized lipi ds and also plays a major role in the metabolism and detoxication of insect icides processed through the cytochrome P450/PON1 pathway. An Arg/Gln (R/Q) substitution at position 192 determines a substrate dependent activity pol ymorphism, In addition to the effect of the amino acid substitution on rate s of hydrolysis of different substrates, there is a large interindividual v ariability in the amount of PON1 protein in sera that is stable over time, Recently, a number of reports based solely on PON1 genotyping have suggeste d that in some populations, the PON1(R192) allele may be a risk factor for coronary artery disease. Another report notes an increased risk of the PON1 (R192) allele for Parkinson's disease. We report here the development of a two-dimensional, microtitre plate reader-based enzyme analysis that provide s a high-throughput assessment of PON1 status. population distribution plot s of diazoxonase Versus paraoxonase activities provides PON1 phenotype and an accurate inference of PON1 genotype. Both are important parameters for d etermining an individual's PON1 status, The analysis also provides PON1 all ele frequencies for specific populations, Pharmacogenetics 9:745-753 (C) 19 99 Lippincott Williams & Wilkins.