Activity of allelic variants of Pi class human glutathione S-transferase toward chlorambucil

Clinical efficacy of alkylating anticancer drugs, such as chlorambucil, is often limited by the emergence of drug resistant tumor cells. Increased glu tathione (GSH) conjugation (inactivation) of alkylating anticancer drugs or their activated metabolites due to overexpression of the Pi class GSH S-tr ansferase (hGSTP1-1) is believed to be an important mechanism in tumor cell resistance to alkylating agents. Interestingly, the hGSTP1 locus is polymo rphic in human populations and involves amino acid residues in positions 10 4 (isoleucine or valine) and/or 113 (alanine or valine). Here, we report th at the allelic variants of hGSTP1-1 significantly differ in their efficienc y in catalyzing the GSH conjugation of chlorambucil. Catalytic efficiency o f the hGSTP1-1(I104,A113) isoform toward chlorambucil was approximately 2.5 -, 7.5- and 15-fold higher compared with I104,V113, V104,A113 and V104,V113 variants of hGSTP1-1, respectively. The results of the present study sugge st that hGSTP1-1 polymorphism may be an important factor in GST-mediated tu mor cell resistance to some alkylating agents. (C) 2000 Academic Press.