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

Xun Hu, Ajai Pal, Jacek Krzeminski, Shantu Amin, Yogesh C. Awasthi, Piotr Zimniak, Shivendra V. Singh

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Abstract

The specificities of human glutathione (GSH) S-transferase (GST) isozymes of class α (hGSTA1-1), μ (hGSTM1-1) and π (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.

Original languageEnglish (US)
Pages (from-to)1685-1689
Number of pages5
JournalCarcinogenesis
Volume19
Issue number9
DOIs
StatePublished - Sep 1 1998

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A 113
Epoxy Compounds
Glutathione Transferase
Isoenzymes
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Protein Isoforms
Molecular Conformation
Stereoisomerism
Benzo(a)pyrene
Polycyclic Aromatic Hydrocarbons
1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene
Human Activities
Carcinogens
Alleles

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Hu, Xun ; Pal, Ajai ; Krzeminski, Jacek ; Amin, Shantu ; Awasthi, Yogesh C. ; Zimniak, Piotr ; Singh, Shivendra V. / Specificities of human glutathione S-transferase isozymes toward anti-diol epoxides of methylchrysenes. In: Carcinogenesis. 1998 ; Vol. 19, No. 9. pp. 1685-1689.
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Specificities of human glutathione S-transferase isozymes toward anti-diol epoxides of methylchrysenes. / Hu, Xun; Pal, Ajai; Krzeminski, Jacek; Amin, Shantu; Awasthi, Yogesh C.; Zimniak, Piotr; Singh, Shivendra V.

In: Carcinogenesis, Vol. 19, No. 9, 01.09.1998, p. 1685-1689.

Research output: Contribution to journalArticle

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T1 - Specificities of human glutathione S-transferase isozymes toward anti-diol epoxides of methylchrysenes

AU - Hu, Xun

AU - Pal, Ajai

AU - Krzeminski, Jacek

AU - Amin, Shantu

AU - Awasthi, Yogesh C.

AU - Zimniak, Piotr

AU - Singh, Shivendra V.

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N2 - The specificities of human glutathione (GSH) S-transferase (GST) isozymes of class α (hGSTA1-1), μ (hGSTM1-1) and π (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.

AB - The specificities of human glutathione (GSH) S-transferase (GST) isozymes of class α (hGSTA1-1), μ (hGSTM1-1) and π (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.

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