The Arg₁₉₂ isoform of paraoxonase with low sarin-hydrolyzing activity is dominant in the Japanese

Abstract

The high-density-lipoprotein-associated enzyme paraoxonase, which has a role in the detoxification of organophosphorus compounds, is known to be polymorphic in humans. The Arg₁₉₂ isoform of paraoxonase hydrolyzes paraoxon more rapidly than the Gln₁₉₂ isoform. However, with respect to the hydrolysis of toxic nerve agents, such as diazoxon, soman, and sarin, the Arg₁₉₂ isoform displays a lower activity than the other isoform. To evaluate the possibility that the genetic polymorphism was involved in the aggravated extent of human injury in the sarin gas poisoning incident in the Tokyo subway in March 1995, we investigated the prevalance of this polymorphism in the Japanese population. We found that the Arg₁₉₂ allele is more common in the Japanese (allele frequency: 0.66) than in people of other races (ranging 0.24–0.31). In the Japanese, 135 out of the 326 subjects (41.4%) investigated were homozygous for the Arg₁₉₂ allele, which shows a very low hydrolysis activity for sarin. Thus, there seems to be a racial difference in vulnerability to toxic nerve agents, such as sarin. The dominance of the Arg₁₉₂ allele in the Japanese population probably worsened the tragedy of March 1995 in the Tokyo subway.