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首页> 外文期刊>Mutation Research. Reviews in Mutation Research >Mammalian class theta GST and differential susceptibility to carcinogens:a review [Review]
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Mammalian class theta GST and differential susceptibility to carcinogens:a review [Review]

机译：哺乳动物类θGST与致癌物的敏感性差异：综述[综述]

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Glutathione S-transferases (GSTs) are an important part of the cellular detoxification system and, perhaps, evolved to protect cells against reactive oxygen metabolites. Theta is considered the most ancient among the GSTs and theta-like GSTs are found in mammals, fish, insects, plants, unicellular algae, and bacteria. It is thought that an ancestral theta-gene underwent an early duplication before the divergence of fungi and animals and further duplications generated the variety of the other classes of GSTs (alpha, mu, phi, etc.). The comparison of the aminoacidic homologies among mammals suggests that a duplication of an ancient GST theta occurred before the speciation of mammals and resulted in the subunits GSTT1 and GSTT2. The ancestral GST theta has a dehalogenase activity towards several halogenated compounds, such as the dichloromethane. In fact, some aerobic and anaerobic methylotrophic bacteria can use these molecules as the sole carbon and energy source. The mammalian GST theta cannot sustain the growth of bacteria but still retains the dehalogenating activity. Therefore, although mammalian GST theta behaves as a scavenger towards electrophiles, such as epoxides, it acts also as metabolic activator for halogenated compounds, producing a variety of intermediates potentially dangerous for DNA and cells. For example, mice exposed to dichloromethane show a dose-dependent incidence of cancer via the GSTT1-1 pathway. Because GSTT1-1 is polymorphic in humans, with about 20% of Caucasians and 80% of Asians lacking the enzyme, the relationship between the phenotype and the incidence of cancer has been investigated extensively in order to detect GSTT1-1-associated differential susceptibility towards endogenous or exogenous carcinogens. The lack of the enzyme is related to a slightly increased risk of cancer of the bladder, gastro-intestinal tract, and for tobacco-related tumors (lung or oral cavity). More pronounced risks were found in males with the GSTT1-null genotype for brain diseases and skin basal cell carcinomas not related to sunlight exposures. Moreover, there was an increased risk of kidney and liver tumors in humans with the GSTT1-1 positive genotype following exposures to halogenated solvents. Interestingly, the liver and kidney are two organs that express the highest level of GST theta in the human body. Thus, the GSTT1-1 genotype is suspected to confer decreased or increased risk of cancer in relation to the source of exposure; in vitro studies, mostly conducted on metabolites of butadiene, confirm the protective action of GSTT1-1, whereas, thus far, experimental studies prove that the increasing risk is limited.
机译：谷胱甘肽S-转移酶（GST）是细胞排毒系统的重要组成部分，也许已经进化为保护细胞免受活性氧代谢物的侵害。 Theta被认为是GST中最古老的，在哺乳动物，鱼类，昆虫，植物，单细胞藻类和细菌中都发现了类似theta的GST。据认为，祖先的theta基因在真菌和动物发散之前经历了早期的复制，进一步的复制产生了其他种类的GST（α，mu，phi等）。哺乳动物之间氨基酸同源性的比较表明，古老的GST theta的复制发生在哺乳动物的物种形成之前，并导致了GSTT1和GSTT2亚基。祖先的GST theta对几种卤代化合物（例如二氯甲烷）具有脱卤酶活性。实际上，一些需氧和厌氧的甲基营养细菌可以将这些分子用作唯一的碳和能源。哺乳动物GST theta无法维持细菌的生长，但仍保留脱卤活性。因此，尽管哺乳动物的GST theta表现为对亲电试剂（例如环氧化物）的清除剂，但它也充当卤代化合物的代谢活化剂，产生了各种可能对DNA和细胞构成危险的中间体。例如，暴露于二氯甲烷的小鼠通过GSTT1-1途径显示出剂量依赖性的癌症发病率。由于GSTT1-1在人类中是多态性的，大约20％的白种人和80％的亚洲人缺乏这种酶，因此为了检测GSTT1-1相关的对人类的易感性，已广泛研究了表型与癌症发生率之间的关系。内源性或外源性致癌物。该酶的缺乏与膀胱癌，胃肠道癌和烟草相关肿瘤（肺或口腔）的患癌风险略有增加有关。在具有GSTT1空基因型的男性中，发现与太阳光照射无关的脑部疾病和皮肤基底细胞癌风险更大。此外，接触卤代溶剂后，GSTT1-1阳性基因型的人患肾脏和肝脏肿瘤的风险增加。有趣的是，肝脏和肾脏是表达人体中最高水平的GST theta的两个器官。因此，怀疑GSTT1-1基因型相对于暴露源具有降低或增加的癌症风险。体外研究（主要是对丁二烯的代谢产物进行的研究）证实了GSTT1-1的保护作用，而到目前为止，实验研究证明，增加的风险是有限的。

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