SPECIFICITIES OF HUMAN GLUTATHIONE-S-TRANSFERASE ISOZYMES TOWARD ANTI-DIOL EPOXIDES OF METHYLCHRYSENES

The specificities of human glutathione (GSH) S-transferase (GST) isozy mes of class alpha (hGSTA1-1), mu (hGSTM1-1) and pi (hGSTP1-1), includ ing the three allelic forms of hGSTP1-1 [hcsTP1-1(I104,A113), hGSTP1-1 (V104,A113) and hGSTP1-1 (V104,V113)], in catalyzing the GSH conjugati on of anti-diol epoxide stereoisomers of 5-methylchrysene (anti-5-MeCD E) have been examined. The specific activities of human GSTs were sign ificantly higher toward (+)anti-5-MeCDE than toward the (-)-enantiomer of anti-5-MeCDE, All three variants of hGSTP1-1 were significantly mo re efficient than either hGSTA1-1 or hGSTM1-1 in GSI-I conjugation of( +)-anti-5-MeCDE, The catalytic efficiencies of hGSTP1-1 variants towar d (+)-anti-5-MeCDE were in the order hGSTP1-1(I104,A113) > hGSTP1-1(V1 04,V113) > hGSTP1-1(V104,A113). The present study suggests that the I1 04,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 sho wn that the hGSTP1-1(V104,V113) isoform is significantly more efficien t than the other two variants of hGSTP1-1 in catalyzing GSH conjugatio n of oxy9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. [(+)-anti-BPDE ], the ultimate carcinogen of benzo[a]pyrene. Even though the mechanis m of the differences in the activities of hGSTP1-1 variants toward ant i-5-MeCDE versus anti-BPDE remains to be elucidated, it seems that the molecular configuration of the diol epoxide is an important determina nt of the activity of hGSTP1-1 isoforms toward polycyclic aromatic hyd rocarbon diol epoxides.