GLUTATHIONE CONJUGATE MEDIATED TOXICITIES
GLUTATHIONE CONJUGATE MEDIATED TOXICITIES
复制标题
DOI：
10.1016/0041-008x(90)90100-9
复制
发表时间：
1990-10-01
影响因子：
3.8
通讯作者：
VANBLADEREN, PJ
中科院分区：
文献类型：
--
作者：
MONKS, TJ;ANDERS, MW;VANBLADEREN, PJ
谷胱甘肽（γ-谷氨酰-L-半胱氨酰甘氨酸；GSH）在大多数活细胞中以高浓度存在，并参与多种重要的细胞反应。特别是，GSH 可以保护细胞免受异生物质代谢形成的潜在有毒亲电子试剂的影响，并且此类反应长期以来一直与解毒过程相关（Baumann 和 Preusse，1879；Jaffe，1879）。形成 GSH 结合物的化合物由 γ-谷氨酰转肽酶 (γ-GT) 和二肽酶加工成半胱氨酸 S-结合物，通常以其相应的硫醇尿酸（S-取代的 N-乙酰基-L-半胱氨酸结合物）的形式在尿液中排泄。此外。 GSH 过氧化物酶活性，无论是由硒依赖性 GSH 过氧化物酶催化还是由 GSH S-转移酶催化，都有助于过氧化氢和有机氢过氧化物的解毒。然而，近年来，越来越多的证据表明，GSH 结合在多种化学物质有毒代谢物的形成中发挥着重要作用。因此，几类化合物通过与 GSH 结合而转化为细胞毒性、基因毒性或诱变代谢物。在 1990 年毒理学学会年会上举办的“谷胱甘肽缀合物介导的毒性”研讨会的目的是讨论这个快速发展的领域的最新发现，提出有关 GSH 缀合物依赖性毒性的机制和调节的想法，就这项工作的更广泛意义达成共识，并确定未来研究的方向。本文总结了这些演讲。 GSH 缀合反应涉及几类外源物质的生物活化，并且可以识别四种类型的 GSH 依赖性生物活化反应：（1）直接有毒的 GSH 缀合物可以通过亲电硫芥子的形成由邻位二卤代烷形成：（2）半胱氨酸缀合物 β-裂合酶依赖性生物活化参与 卤代烯烃的选择性肾毒性； (3) 对苯二酚和异硫氰酸酯的 GSH 结合物可作为转运和靶向代谢物； （4）GSH依赖性反应可能涉及前体有机硫氰酸盐和亚硝基胍（N-甲基-N'-硝基-N-亚硝基胍）释放有毒物质。
Glutathione (γ-glutamyl-l-cysteinylglycine; GSH) is present in high concentrations in most living cells and participates in a variety of vital cellular reactions. In particular, GSH protects cells from potentially toxic electrophiles formed via the metabolism of xenobiotics, and such reactions have long been associated with the process of detoxication (Baumann and Preusse. 1879; Jaffe, 1879). Compounds that form GSH conjugates are processed by γ-glutamyl transpeptidase (γ-GT) and dipeptidases to cysteine S-conjugates, which are usually excreted in urine as their corresponding mercapturic acids (S-substituted N-acetyl-l-cysteine conjugates). In addition. GSH peroxidase activity, whether catalyzed by the selenium-dependent GSH peroxidase or by the GSH S-transferases, serves to detoxify hydrogen peroxide and organic hydroperoxides. However, in recent years, evidence indicating that GSH conjugation plays an important role in the formation of toxic metabolites from a variety of chemicals has accumulated. Thus, several classes of compounds are converted, via conjugation with GSH, into either cytotoxic, genotoxic, or mutagenic metabolites. The purposes of the symposium on “Glutathione Conjugate Mediated Toxicities” presented at the 1990 Society of Toxicology Annual Meeting were to discuss recent findings in this rapidly moving field, to present ideas on the mechanisms and modulation of GSH conjugate-dependent toxicities, to present a consensus on the broader significance of this work, and to identify directions for future research. This paper summarizes these presentations. GSH conjugation reactions are involved in the bioactivation of several classes of xenobiotics, and four types of GSH-dependent bioactivation reactions can be identified: (1) directly toxic GSH conjugates may be formed from vicinal dihaloalkanes via formation of electrophilic sulfur mustards: (2) cysteine conjugate β-lyase-dependent bioactivation is involved in the selective nephrotoxicity of haloalkenes; (3) GSH conjugates of hydroquinones and isothiocyanates may serve as transport and targeting metabolites; and (4) GSH-dependent reactions may be involved in the release of toxic agents from precursor organic thiocyanates and nitrosoguanidines (N-methyl-N′-nitro-N-nitrosguanidine).