Specificities of human glutathione S-transferase isozymes toward anti-diol epoxides of methylchrysenes.

The specificities of human glutathione (GSH) S-transferase (GST) isozymes of class alpha (hGSTA1-1), mu (hGSTM1-1) and pi (hGSTP1-1), including the three allelic forms of hGSTP1-1 [hGSTP1-1(I104,A113), hGSTP1-1(V104,A113) and hGSTP1-1(V104,V113)], in catalyzing the GSH conjugation of anti-diol epoxide stereoisomers of 5-methylchrysene (anti-5-MeCDE) have been examined. The specific activities of human GSTs were significantly higher toward (+)-anti-5-MeCDE than toward the (-)-enantiomer of anti-5-MeCDE. All three variants of hGSTP1-1 were significantly more efficient than either hGSTA1-1 or hGSTM1-1 in GSH conjugation of (+)-anti-5-MeCDE. The catalytic efficiencies of hGSTP1-1 variants toward (+)-anti-5-MeCDE were in the order hGSTP1-1(I104,A113) > hGSTP1-1(V104,V113) > hGSTP1-1(V104,A113). The present study suggests that the I104,A113 allele, which is most frequent in human populations, may play a major role in the detoxification of (+)-anti-5-MeCDE. This may point to specificity, because previous studies from our laboratory have shown that the hGSTP1-1(V104,V113) isoform is significantly more efficient than the other two variants of hGSTP1-1 in catalyzing GSH conjugation of (+)-anti-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene [(+)-anti-BPDE], the ultimate carcinogen of benzo[a]pyrene. Even though the mechanism of the differences in the activities of hGSTP1-1 variants toward anti-5-MeCDE versus anti-BPDE remains to be elucidated, it seems that the molecular configuration of the diol epoxide is an important determinant of the activity of hGSTP1-1 isoforms toward polycyclic aromatic hydrocarbon diol epoxides.