Pemble S, Schroeder K R, Spencer S R, Meyer D J, Hallier E, Bolt H M, Ketterer B, Taylor J B
Department of Biochemistry and Molecular Biology, University College London, U.K.
Biochem J. 1994 May 15;300 ( Pt 1)(Pt 1):271-6. doi: 10.1042/bj3000271.
In humans, glutathione-dependent conjugation of halomethanes is polymorphic, with 60% of the population classed as conjugators and 40% as non-conjugators. We report the characterization of the genetic polymorphism causing the phenotypic difference. We have isolated a cDNA that encodes a human class Theta GST (GSTT1) and which shares 82% sequence identity with rat class Theta GST5-5. From PCR and Southern blot analyses, it is shown that the GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse. In humans, the enzyme is found in the erythrocyte and this may act as a detoxification sink. Characterization of the GSTT1 polymorphism will thus enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.
在人类中，卤代甲烷的谷胱甘肽依赖性结合具有多态性，60%的人群被归类为结合者，40%为非结合者。我们报告了导致表型差异的基因多态性的特征。我们分离出了一个编码人类θ类谷胱甘肽S-转移酶（GSTT1）的cDNA，它与大鼠θ类谷胱甘肽S-转移酶5-5具有82%的序列同一性。通过PCR和Southern印迹分析表明，38%的人群中不存在GSTT1基因。GSTT1基因的存在与否分别与结合者（GSST1+）和非结合者（GSTT1-）表型一致。GSTT1+表型可以催化二氯甲烷的谷胱甘肽结合，这一代谢途径在鼠伤寒沙门氏菌致突变性测试菌株中已被证明具有致突变性，并且被认为是二氯甲烷在小鼠中致癌性的原因。在人类中，该酶存在于红细胞中，这可能起到解毒作用。因此，对GSTT1多态性的表征将能够更准确地评估合成卤代甲烷和其他工业化学品对人类健康的风险。
