Wiencke J K, Kelsey K T, Lamela R A, Toscano W A
Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco 94143.
Cancer Res. 1990 Mar 1;50(5):1585-90.
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 mu-isozyme of the glutathione (GSH) S-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 trans-stilbene oxide, an excellent substrate for GSH S-transferase mu, 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 mu 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 mu, 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 stilbene oxide illustrate that the stereoselectivity of GSH S-transferase mu toward various alkene epoxide substrates can be an important factor affecting individual sensitivity to DNA-damaging epoxides.
识别使个体易患环境诱导型癌症的遗传特征是癌症风险评估中最重要的问题之一。谷胱甘肽（GSH）S-转移酶（EC 2.5.1.18）的μ-同工酶基因缺陷最近被认为与肺癌风险增加有关。为了检验这种关联是否源于对诱变底物的代谢介导敏感性，我们诱导了21名同工酶缺陷个体和24名非缺陷个体淋巴细胞中的细胞遗传学损伤。细胞用反式氧化茋处理，反式氧化茋是GSH S-转移酶μ的优良底物，或用顺式氧化茋处理，顺式氧化茋是该同工酶的不良底物。测量姐妹染色单体交换诱导情况作为细胞遗传学损伤的指标。在人群中观察到反式氧化茋诱导的姐妹染色单体交换呈三峰分布，包括抗性、中度和高度敏感组。谷胱甘肽S-转移酶μ缺陷与对反式氧化茋诱导损伤的中度和高度敏感性相关，但对顺式氧化茋诱导的姐妹染色单体交换没有影响。结果表明，谷胱甘肽S-转移酶μ作为一种提议的癌症易感性标志物，也是对某类诱变剂诱导细胞遗传学损伤易感性的标志物。氧化茋顺反异构体的不同作用表明，谷胱甘肽S-转移酶μ对各种烯烃环氧化物底物的立体选择性可能是影响个体对DNA损伤环氧化物敏感性的一个重要因素。
