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  • Title: Catalytic efficiencies of allelic variants of human glutathione S-transferase P1-1 toward carcinogenic anti-diol epoxides of benzo[c]phenanthrene and benzo[g]chrysene.
    Author: Hu X, Xia H, Srivastava SK, Pal A, Awasthi YC, Zimniak P, Singh SV.
    Journal: Cancer Res; 1998 Dec 01; 58(23):5340-3. PubMed ID: 9850062.
    Abstract:
    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 I104,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) x s(-1), was approximately 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).
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