The Arg 192 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.

Death due to Poisoning - a Medicolegal Study at Dhaka Medical College, Dhaka

“…Chronic exposure to OPC also gives rise to a condition called COPINDChronic Organo Phosphate induced neuro-psychiatric disorder [15][16][17] . Genetic differences also play important role in Chronic OPC poisoning cases 18 .…”

Factors in genetic susceptibility in a chemical sensitive population using QEESI

“…Statistical power calculations were performed using Epistat (Finnish Institute of Occupational Health). This study sample size had at least 80% power (two-sided test significant, a of 0.05) to detect an OR of at least 2.5, following the calculations used in previous studies [18][19][20]. We used the dominant model for GSTM1 and GSTT1 and the recessive model for ALDH2 and PON1 in the test analysis.…”

“…The genotypes of ALDH2 (rs671) were identified by the method of Harada and Zhang [13] as the homozygous genotype of normal ALDH2 (*1/*1), the homozygous genotype of inactive ALDH2 (*2/*2), and the heterozygous genotype of normal and inactive ALDH2 (*1/*2). The genotype of the Gln192Arg (rs662) polymorphism of the PON1 gene was determined essentially as described previously [19].…”

Effects of the Endothelin Receptor Antagonist Bosentan on Hemodynamics, Symptoms and Functional Capacity in Japanese Patients With Severe Pulmonary Hypertension

“…Numerous clinical studies have shown that ethnic groups may differ in their responsiveness to drugs, [25][26][27] and it has also been suggested that racial differences in the catalytic activity of cytochrome P450 (CYP) isozyme may be responsible for the differences in drug kinetics. 28 The International Conference on Harmonization guideline (ICHE5) document "Ethnic Factors in the Acceptability of Foreign Data" recommends the measurement of pharmacokinetic/pharmacodynamic parameters to permit the clinical effects obtained in one population to be extrapolated to a different population.…”