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Catalytic Efficiencies of Allelic Variants of Human Glutathione S-transferase P1-1 toward Carcinogenic anti-Diol Epoxides of Benzo[c]phenanthrene and Benzo[g]chrysene¹

Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15219 [X. H., H. X., S. K. S., A. P., S. V. S.]; Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, Texas 77555 [Y. C. A.]; and Departments of Medicine, and Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences and McClellan Veterans Affairs Hospital Medical Research, Little Rock, Arkansas 72205 [P. Z.]

Four allelic variants of glutathione (GSH) S-transferase P1-1 (hGSTP1-1) that differ in their structures at amino acid(s) in position(s) 104 and/or 113 are known to exist in human populations. However, the physiological significance of hGSTP1-1 polymorphism is not fully understood. In this communication, we report that the 1104,A113 allele of hGSTP1-1, which is most frequent in human populations, is also most efficient in the GSH conjugation of carcinogenic anti-diol epoxides of benzo[g]chrysene and benzo[c]phenanthrene (anti-BGCDE and anti-BCPDE, respectively). The catalytic efficiency of hGSTP1-1(I104,A113) isoform toward anti-BGCDE, 0.36 mM^-1·s^-1, was 1.7-fold higher (P < 0.05) compared with hGSTP1-1(V104,V113). Interestingly, the frequency of codon 104-valine alleles is significantly higher in certain cancers compared with codon 104-isoleucine alleles. Like anti-BGCDE, the catalytic efficiency of hGSTP1-1(I104,A113) isoform toward anti-BCPDE was higher by about 1.4- to 2.2-fold (P < 0.05) than those of other hGSTP1-1 variants. These observations are interesting because we have shown previously (Hu, X. et al., Biochem. Biophys. Res. Commun., 238: 397–402, 1997) that the V104,V113 variant, not the I104,A113 isoform, is most efficient in the GSH conjugation of bay-region anti-diol epoxide of benzo(a)pyrene (anti-BPDE), which, unlike anti-BGCDE or anti-BCPDE, is a planar molecule. In conclusion, our results suggest that hGSTP1-1 polymorphism may be an important factor in differential susceptibility of humans to cancers where polycyclic aromatic hydrocarbons are etiological factors and that I104,A113 variant may play a major role in the detoxification of nonplanar, sterically hindered fjord-region diol epoxides (e.g., anti-BGCDE).

¹ Supported in part by USPHS Grants ES 09140, CA 55589, and 76348 (to S. V. S.); ES 07804 (to P. Z.); and CA 27967 (to Y. C. A.).

² To whom requests for reprints should be addressed, at Cancer Research Laboratory, The Mercy Hospital, 1400 Locust Street, Pittsburgh, PA 15219.

Received 7/15/98. Accepted 10/13/98.

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