Carcinogenesis, Vol. 20, No. 10, 1997-2001,
October 1999
© 1999 Oxford University Press
Carcinogenesis |
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
Cancer Research Laboratory, Mercy Cancer Institute, Mercy Hospital of Pittsburgh, Pittsburgh, PA 15219, USA and
1 Institute of Toxicology, University of Mainz, Obere Zahlbacher Strasse 67, D-55131, Mainz, Germany
Specificities of murine glutathione (GSH) S-transferase (GST) isozymes mGSTA1-1, mGSTA2-2, mGSTA3-3 and mGSTA4-4 (
class), mGSTP1-1 (
class) and mGSTM1-1 (µ 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 µM) 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 (kcat/Km) of mGSTA1-1 towards (–)-anti-B[g]CDE was ~2.3- to 16.6-fold higher compared with other murine GSTs. Likewise, mGSTA1-1 was ~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 , was virtually inactive towards both stereoisomers of B[g]CDE. The results of the present study indicate that murine GSTs, especially 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.
Abbreviations: B[g]C, benzo[g] chrysene; B[g]CDE, benzo[g]chrysene 11,12-diol 13,14-epoxide; BPDE, benzo[a]pyrene 7,8-diol 9,10-epoxide; GSH, glutathione; GST, glutathione S-transferase; PAHs, polycyclic aromatic hydrocarbons.
2 Present address: Biochemical Institute for Environmental Carcinogens, Prof. Dr Gernot Grimmer Foundation, Lurup 4, D-22927 Grosshansdorf, Germany
3 To whom correspondence should be addressedEmail: ssingh{at}mercy.pmhs.org
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