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.
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).
authors.affiliation: Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, Pennsylvania 15219, USA.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: H
authors.initials: H
authors.lastname: Xia
authors.forename: S K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: A
authors.initials: A
authors.lastname: Pal
authors.forename: Y C
authors.initials: YC
authors.lastname: Awasthi
authors.forename: P
authors.initials: P
authors.lastname: Zimniak
authors.forename: S V
authors.initials: SV
authors.lastname: Singh
mesh_terms: D000483:Alleles; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D002911:Chrysenes / Q000378:metabolism* / Q000493:pharmacokinetics; D014644:Genetic Variation; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D010616:Phenanthrenes / Q000378:metabolism* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D002273:Carcinogens; D002911:Chrysenes; D007527:Isoenzymes; D010616:Phenanthrenes; C090203:1,2-epoxy-3,4-dihydroxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene; C089231:benzo(g)chrysene-11,12-dihydrodiol-13,14-epoxide; D005982:Glutathione Transferase; D005978:Glutathione