The identification of genetic traits that predispose individuals to environmentally induced cancers is one of the most important problems in cancer risk assessment. Genetic deficiency in the µ-isozyme of the glutathione (GSH) S-transferases (EC has recently been associated with increased lung cancer risk. To test whether this association could arise from a metabolically mediated sensitivity to mutagenic substrates, cytogenetic damage in lymphocytes from 21 isozyme-deficient and 24 nondeficient individuals was induced. Cells were treated with trans-stilbene oxide, an excellent substrate for GSH S-transferase µ, or cis-stilbene oxide, a poor substrate for the isozyme. Sister chromatid exchange induction was measured as an indicator of cytogenetic damage. A trimodal distribution of trans-stilbene oxide-induced sister chromatid exchanges was observed in the population, including resistant, moderate, and highly sensitive groups. Glutathione S-transferase µ deficiency was associated with both moderate and high sensitivity to trans-stilbene oxide-induced damage but had no effect on cis-stilbene oxide-induced sister chromatid exchange. The results indicate that GSH S-transferase µ, a proposed marker of cancer susceptibility, is also a marker of susceptibility to the induction of cytogenetic damage by a certain class of mutagens. The differential effects of the cis- and trans-isomers of stillbene oxide illustrate that the stereoselectivity of GSH S-transferase µ toward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.


This work was supported in part by USPHS Grant P02 CA 43764 from the National Cancer Institute, Bethesda, MD (J. K. W.), by USPHS Grant GM/ES-02866 (W. A. T.), by Center Grant ES-0002 from the National Institutes of Health, Bethesda, MD (W. A. T., K. T. K.), by a Faculty Development Award, Mellon Foundation (K. T. K.), and by the Office of Health and Environmental Research, United States Department of Energy Contract DE-AC03-76-SF01012 (J. K. W.).

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