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Another Jekyll and Hyde story?

Glutathione S-transferases (EC 2.5.1.18) in mammalian cells catalyse the conjugation, and thus, the detoxification of a structurally diverse group of electrophilic environmental carcinogens and alkylating drugs, including the antineoplastic nitrogen mustards. We proposed that structural alteration of the nonspecific electrophile-binding site would produce mutant enzymes with increased efficiency for detoxification of a single drug and that these mutants could serve as useful somatic transgenes to protect healthy human cells against single alkylating agents used in cancer chemotherapy protocols. Random mutagenesis of three regions (residues 9 14, 102 -112, and 210 220), which together compose the glutathione S-transferase electrophilebinding site, followed by selection of Escherichia coli expressing the enzyme library with the nitrogen mustard mechlorethamine (20 500 ,uM), yielded mutant enzymes that showed significant improvement in catalytic efficiency for mechlorethamine conjugation (up to 15-fold increase in K,a, and up to sixfold increase in K~at~Km) and that confer up to 31fold resistance, which is ninefold greater drug resistance than that conferred by the wild type enzyme. The results suggest a general strategy for modification of drugand carcinogen-metabolizing enzymes to achieve desired resistance in both prokaryotic and eukaryotic plant and animal cells.