title: Differential enantioselectivity of murine glutathione S-transferase isoenzymes in the glutathione conjugation of trans-3,4-dihydroxy-1, 2-oxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene stereoisomers.
abstract: The kinetics of the glutathione (GSH) conjugation of (+)- and (-)-enantiomers of anti- as well as syn-3,4-dihydroxy-1,2-oxy-1,2,3, 4-tetrahydrobenzo[c]phenanthrene (B[c]PDE) catalyzed by murine GSH S-transferase (GST) isoenzymes has been investigated. Murine GSTs exhibited significant differences in their enantioselectivity toward B[c]PDE stereoisomers. For example, while pi class isoenzyme mGSTP1-1 was virtually inactive toward stereoisomers with 1S configuration [(-)-syn-and (+)-anti-B[c]PDE], these stereoisomers were good substrates for alpha class isoenzyme mGSTA1-2. When GST activity was measured as a function of varying B[c]PDE concentration (10-320 microM) at a fixed saturating concentration of GSH (2 mM), each isoenzyme examined obeyed Michaelis-Menten kinetics with all four B[c]PDE stereoisomers. Alpha class isoenzyme mGSTA4-4 exhibited negligible activity toward all four stereoisomers of B[c]PDE. The catalytic efficiency of mGSTA1-2 was approximately 1.5- to 15-fold higher than other murine GSTs in the GSH conjugation of (-)-anti-B[c]PDE, which among the four B[c]PDE stereoisomers is the most potent pulmonary carcinogen in the newborn mouse model and a potent skin tumor-initiator. While alpha class isoenzymes mGSTA3-3 and mGSTA1-2 were equally efficient in the GSH conjugation of (+)-anti-B[c]PDE, their catalytic efficiencies toward this stereoisomer were significantly higher than those of mGSTP1-1 and mGSTM1-1. Likewise, mGSTA1-2 was relatively more efficient than other GSTs in the GSH conjugation of both enantiomers of syn-B[c]PDE. In summary, our results indicate that (a) murine GSTs significantly differ in their enantioselectivity in the GSH conjugation of B[c]PDE stereoisomers, which may partially account for the observed differences in the carcinogenic potency of B[c]PDE stereoisomers, and (b) mGSTA1-2 and mGSTA3-3 play a major role in the detoxification of B[c]PDE.
authors.affiliation: Mercy Cancer Institute, The Mercy Hospital of Pittsburgh, 1400 Locust Street, Pittsburgh, Pennsylvania, 15219, USA.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.forename: A
authors.initials: A
authors.lastname: Seidel
authors.forename: H
authors.initials: H
authors.lastname: Frank
authors.forename: S K
authors.initials: SK
authors.lastname: Srivastava
authors.forename: H
authors.initials: H
authors.lastname: Xia
authors.forename: A
authors.initials: A
authors.lastname: Pal
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.forename: F
authors.initials: F
authors.lastname: Oesch
authors.forename: S V
authors.initials: SV
authors.lastname: Singh
mesh_terms: D000818:Animals; D002274:Carcinogens, Environmental / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D005978:Glutathione / Q000737:chemistry* / Q000378:metabolism; D005982:Glutathione Transferase / Q000737:chemistry* / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D010616:Phenanthrenes / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D002274:Carcinogens, Environmental; D007527:Isoenzymes; D010616:Phenanthrenes; C090203:1,2-epoxy-3,4-dihydroxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene; D005982:Glutathione Transferase; D005978:Glutathione