Human Glutathione 5"-Transferase Deficiency as a Marker of Susceptibility to Epoxide-induced Cytogenetic Damage1

The identification of genetic traits that predispose individuals to envi ronmentally induced cancers is one of the most important problems in cancer risk assessment. Genetic deficiency in the jj-isozyme of the glutathione (GSH) 5-transferases (EC 2.5.1.18) 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 tranxstilbene oxide, an excellent substrate for GSH 5-transferase n, or cisstilbene oxide, a poor substrate for the isozyme. Sister eliminatili ex change induction was measured as an indicator of cytogenetic damage. A trimodal distribution of min.v-stilhcnc oxide-induced sister chromatid exchanges was observed in the population, including resistant, moderate, and highly sensitive groups. Glutathione 5-transferase Mdeficiency was associated with both moderate and high sensitivity to rrans-stilbene oxide-induced damage but had no effect on c/s-stilbene oxide-induced sister chromatid exchange. The results indicate that GSH 5-transferase n, 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 t-i'.vand rrans-isomers of stilbene oxide illustrate that the stereoselectivity of GSH 5-transferase Mtoward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.