Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.
College of Environment and Resource, Shanxi University, Taiyuan, Shanxi, China.
Adv Exp Med Biol. 2018;1032:37-53. doi: 10.1007/978-3-319-98788-0_3.
Glutathione (GSH) is the most abundant non-protein thiol, attaining cellular concentrations in the millimolar range. GSH functions to protect cells against endogenous and exogenous electrophiles. In addition, GSH serves as a cofactor for the GSH peroxidase family of enzymes which metabolize HO as well as lipid peroxides. Through the action of glutathione S-transferase family of enzymes, GSH is conjugated to a variety of electrophilic endogenous compounds and exogenous chemicals, and thereby facilitates their efficient and safe elimination. Through the transsulfuration pathway, GSH biosynthesis is metabolically linked with cellular methylation, which is pivotal for epigenetic gene regulation. Accumulating evidence suggests that the underlying mechanisms of alcohol-associated tissue injury and carcinogenesis involve: (i) generation of the electrophilic metabolite acetaldehyde, (ii) induction of CYP2E1 leading to the formation of reactive oxygen species and pro-carcinogen activation, and (iii) nutritional deficiencies, such as methyl groups, resulting in enhanced susceptibility to cancer development. In this context, clinical and experimental investigations suggest an intimate involvement of GSH and related enzymes in the development of alcohol-induced pathological conditions. The aim of this review is to provide an overview of the GSH biosynthesis, cellular transsulfuration/transmethylation pathways, and their implications in the pathogenesis and treatment of alcohol-related disease and cancer.
谷胱甘肽（GSH）是最丰富的非蛋白巯基，细胞内浓度达到毫摩尔级。GSH 的功能是保护细胞免受内源性和外源性亲电试剂的侵害。此外，GSH 作为 GSH 过氧化物酶家族的辅因子，代谢 HO 以及脂质过氧化物。通过谷胱甘肽 S-转移酶家族的酶的作用，GSH 与各种亲电内源性化合物和外源性化学物质结合，从而促进其有效和安全的消除。通过转硫途径，GSH 的生物合成与细胞甲基化代谢相关，这对于表观遗传基因调控至关重要。越来越多的证据表明，与酒精相关的组织损伤和致癌作用的潜在机制涉及：（i）亲电代谢物乙醛的生成，（ii）CYP2E1 的诱导导致活性氧和前致癌物的形成和激活，以及（iii）营养缺乏，如甲基，导致癌症发展的易感性增加。在这种情况下，临床和实验研究表明 GSH 及其相关酶在酒精引起的病理状态的发展中密切相关。本综述的目的是概述 GSH 的生物合成、细胞转硫/转甲基途径及其在酒精相关疾病和癌症发病机制和治疗中的意义。
