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Differences in Stereoselectivity and Catalytic Efficiency of Three Human Glutathione Transferases in the Conjugation of Glutathione with 7ß,8-Dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene¹

Department of Toxicology, Karolinska Institute, Doktorsringen 16, S-104 01 Stockholm, [I. G. C. R., B. J.] and Department of Biochemistry, Arrhenius Laboratory, University of Stockholm, S-106 91 Stockholm, Sweden, [C. G., B. M.]

The kinetics of the enzyme-catalyzed conjugation of glutathione with (±)-7ß,8-dihydroxy-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene [(±)-anti-BPDE] have been studied with the following human cytosolic glutathione transferases: the basic (-) and near-neutral (µ) isoenzymes from liver, and the acidic () isoenzyme from placenta. When the BPDE concentration was varied (using 5 mM glutathione) the apparent V_max values for transferases -, µ, and were 38, 570, and 825 nmol·mg^-1. min^-1, respectively, with corresponding apparent K_m values of 88, 27, and 54 µM. The apparent K_m values for glutathione [using 80 µM (±)-anti-BPDE] were 0.4, 0.7, and 0.1 mM for transferases -, µ, and , respectively. The glutathione conjugates formed with the two enantiomers of (±)-anti-BPDE were resolved by high performance liquid chromatography. The percentages of conjugates derived from the highly carcinogenic (+)-enantiomer were 59, 60, and 90% for transferases -, µ, and , respectively. The separate enantiomers of anti-BPDE were assayed in experiments with transferases µ and . Both enantiomers were substrates for transferase µ, but only the (+)-enantiomer gave measurable activity with transferase µ. A 3-fold increase in V_max and K_m values for transferase was obtained with (+)-anti-BPDE as compared with the racemic substrate and could be quantitatively accounted for by the finding that (-)-anti-BPDE serves as a competitive inhibitor for transferase .

¹ This work was supported by grants from the Swedish Tobacco Company, the Swedish Cancer Society, and the Swedish Council for Planning and Coordination of Research.

² Present address: United States Environmental Protection Agency, Research Triangle Park, NC 27711.

³ To whom requests for reprints should be addressed.

Received 7/16/85. Revised 1/ 7/86. Accepted 1/13/86.

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