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

Specificities of murine glutathione (GSH) S-transferase (GST) isozymes mGST A1-1, mGSTA2-2, mGSTA3-3 and mGSTA4-4 (alpha class), mGSTP1-1 (pi class) an d mGSTM1-1 (mu class) for GSH conjugation of (-)-anti- and (+)-syn-stereois omers 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 mu M) at a fixed saturat ing concentration of GSH (2 mM), each isozyme obeyed Michaelis-Menten kinet ics. mGSTA1-1 was significantly more efficient than other murine GSTs in th e GSH conjugation of not only (-)-anti-stereoisomer but also (+)-syn-B[g]CD E. For example, the catalytic efficiency (k(cat)/K-m) of mGSTA1-1 towards ( -)-anti-B[g]CDE was similar to 2.3- to 16.6-fold higher compared with other murine GSTs, Likewise, mGSTA1-1 was similar to 2.7-, 6.7-, 4.4- and 12.4-f old more efficient than mGSTA2-2, mGSTA3-3, mGSTP1-1 and mGSTM1-1, respecti vely, in catalyzing the GSH conjugation of (+)-syn-B[g]CDE. Interestingly, mGSTA4-4, which also belongs to class a, was virtually inactive towards bot h stereoisomers of B[g]CDE, The results of the present study indicate that murine GSTs, especially a class isozymes, significantly differ in their abi lity 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 f our B[g]CDE stereoisomers are formed from the carcinogen B[g]C as major DNA binding metabolites.