title: Specificity of murine glutathione S-transferase isozymes in the glutathione conjugation of (-)-anti- and (+)-syn-stereoisomers of benzo[g]chrysene 11,12-diol 13,14-epoxide.
abstract: Specificities of murine glutathione (GSH) S-transferase (GST) isozymes mGSTA1-1, mGSTA2-2, mGSTA3-3 and mGSTA4-4 (alpha class), mGSTP1-1 (pi class) and mGSTM1-1 (mu class) for GSH conjugation of (-)-anti- and (+)-syn-stereoisomers of benzo[g]chrysene 11, 12-diol 13,14-epoxide (B[g]CDE), the activated metabolites of the environmental pollutant benzo[g]chrysene (B[g]C), have been determined. When GST activity was determined as a function of varying (-)-anti- or (+)-syn-B[g]CDE concentration (10-320 microM) at a fixed saturating concentration of GSH (2 mM), each isozyme obeyed Michaelis-Menten kinetics. mGSTA1-1 was significantly more efficient than other murine GSTs in the GSH conjugation of not only (-)-anti-stereoisomer but also (+)-syn-B[g]CDE. For example, the catalytic efficiency (k(cat)/K(m)) of mGSTA1-1 towards (-)-anti-B[g]CDE was approximately 2.3- to 16.6-fold higher compared with other murine GSTs. Likewise, mGSTA1-1 was approximately 2.7-, 6.7-, 4.4- and 12.4-fold more efficient than mGSTA2-2, mGSTA3-3, mGSTP1-1 and mGSTM1-1, respectively, in catalyzing the GSH conjugation of (+)-syn-B[g]CDE. Interestingly, mGSTA4-4, which also belongs to class alpha, was virtually inactive towards both stereoisomers of B[g]CDE. The results of the present study indicate that murine GSTs, especially alpha class isozymes, significantly differ in their ability to detoxify B[g]CDE stereoisomers and that mGSTA1-1 plays a major role in the detoxification of both (-)-anti- and (+)-syn-B[g]CDE, which among four B[g]CDE stereoisomers are formed from the carcinogen B[g]C as major DNA binding metabolites.
authors.affiliation: Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pal
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.forename: H
authors.initials: H
authors.lastname: Xia
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: S K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: F
authors.initials: F
authors.lastname: Oesch
authors.forename: S V
authors.initials: SV
authors.lastname: Singh
mesh_terms: D000818:Animals; D002384:Catalysis; D002911:Chrysenes / Q000493:pharmacokinetics*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D009153:Mutagens / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D002911:Chrysenes; D007527:Isoenzymes; D009153:Mutagens; C089231:benzo(g)chrysene-11,12-dihydrodiol-13,14-epoxide; D005982:Glutathione Transferase; D005978:Glutathione