The human serum paraoxonase/arylesterase polymorphism.

The heterozygous human serum paraoxonase phenotype can be clearly distinguished from both homozygous phenotypes on the basis of its distinctive ratio of paraoxonase to arylesterase activities. A trimodal distribution of the ratio values was found with 348 individual serum samples, measuring the ratio of paraoxonase activity (with 1 M NaCl in the assay) to arylesterase activity, using phenylacetate. The three modes corresponded to the three paraoxonase phenotypes, A, AB, and B (individual genotypes), and the expected Mendelian segregation of the trait was observed within families. The paraoxonase/arylesterase activity ratio showed codominant inheritance. We have defined the genetic locus determining the aromatic esterase (arylesterase) responsible for the polymorphic paraoxonase activity as esterase-A (ESA) and have designated the two common alleles at this locus by the symbols ESAA and ESAB. The frequency of the ESAA allele was estimated to be .685, and that of the ESAB allele, 0.315, in a sample population of unrelated Caucasians from the United States. We postulate that a single serum enzyme, with both paraoxonase and arylesterase activity, exists in two different isozymic forms with qualitatively different properties, and that paraoxon is a "discriminating" substrate (having a polymorphic distribution of activity) and phenylacetate is a "nondiscriminating" substrate for the two isozymes. Biochemical evidence for this interpretation includes the cosegregation of the degree of stimulation of paraoxonase activity by salt and paraoxonase/arylesterase activity ratio characteristics; the very high correlation between both the basal (non-salt stimulated) and salt-stimulated paraoxonase activities with arylesterase activity; and the finding that phenylacetate is an inhibitor for paraoxonase activities in both A and B types of enzyme.