Lau S S, Hill B A, Highet R J, Monks T J
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin 78712.
Mol Pharmacol. 1988 Dec;34(6):829-36.
The chemical reaction of 1,4-benzoquinone with glutathione results in the formation of adducts that exhibit increasing degrees of glutathione substitution. Purification of these adducts and analysis by 1H and 13C nuclear magnetic resonance spectroscopy revealed the products of the reaction to be 2-(glutathion-S-yl)hydroquinone; 2,3-(diglutathion-S-yl)hydroquinone; 2,5-(diglutathion-S-yl)hydroquinone; 2,6(diglutathion-S-yl)hydroquinone; 2,3,5-(triglutathion-S-yl)hydroquinone; and 2,3,5,6-(tetraglutatathion-S-yl)hydroquinone. The initial conjugation of 1,4-benzoquinone with glutathione did not significantly affect the oxidation potential of the compound. However, subsequent oxidation and glutathione addition resulted in the formation of conjugates that, dependent upon the position of addition, become increasingly more difficult to oxidize. Increased glutathione substitutions, which resulted in an increase in oxidation potentials, paradoxically resulted in enhanced nephrotoxicity. The triglutathion-S-yl conjugate was the most potent nephrotoxicant; the diglutathion-S-yl conjugates exhibited similar degrees of nephrotoxicity; the mono- and tetraglutathion-S-yl conjugates were not toxic. Thus, with the exception of the fully substituted isomer, the severity of renal necrosis correlated with the extent of glutathione substitution. The lack of toxicity of the fully substituted isomer is probably a consequence of its inability to alkylate tissue components. Thus, the conjugation of glutathione with quinones does not necessarily result in detoxification, even when the resulting conjugates are more stable to oxidation. The inhibition of gamma-glutamyl transpeptidase by AT-125 protected against 2,3,5-(triglutathion-S-yl)hydroquinone-mediated nephrotoxicity. It is suggested that other extra-renal sites expressing relatively high levels of gamma-glutamyl transpeptidase might therefore also be susceptible to hydroquinone-linked glutathione conjugate toxicity. This pathway might also contribute to the carcinogenicity and mutagenicity of certain quinones.
1,4 - 苯醌与谷胱甘肽的化学反应会生成加合物，这些加合物呈现出不同程度的谷胱甘肽取代。对这些加合物进行纯化，并通过氢核磁共振光谱和碳 - 13核磁共振光谱分析，结果表明该反应的产物为2 - （谷胱甘肽 - S - 基）对苯二酚；2,3 - （二谷胱甘肽 - S - 基）对苯二酚；2,5 - （二谷胱甘肽 - S - 基）对苯二酚；2,6 - （二谷胱甘肽 - S - 基）对苯二酚；2,3,5 - （三谷胱甘肽 - S - 基）对苯二酚；以及2,3,5,6 - （四谷胱甘肽 - S - 基）对苯二酚。1,4 - 苯醌与谷胱甘肽的初始共轭作用并未显著影响该化合物的氧化电位。然而，随后的氧化和谷胱甘肽添加导致形成共轭物，根据添加位置的不同，这些共轭物越来越难以被氧化。谷胱甘肽取代程度的增加导致氧化电位升高，但矛盾的是却增强了肾毒性。三谷胱甘肽 - S - 基共轭物是最有效的肾毒物；二谷胱甘肽 - S - 基共轭物表现出相似程度的肾毒性；单谷胱甘肽 - S - 基和四谷胱甘肽 - S - 基共轭物无毒。因此，除了完全取代的异构体之外，肾坏死的严重程度与谷胱甘肽取代程度相关。完全取代异构体缺乏毒性可能是由于其无法使组织成分烷基化。因此，谷胱甘肽与醌的共轭作用不一定会导致解毒，即使生成的共轭物对氧化更稳定。AT - 125对γ - 谷氨酰转肽酶的抑制作用可预防2,3,5 - （三谷胱甘肽 - S - 基）对苯二酚介导的肾毒性。因此，有人认为其他表达相对高水平γ - 谷氨酰转肽酶的肾外部位可能也易受对苯二酚连接的谷胱甘肽共轭物毒性的影响。该途径也可能导致某些醌的致癌性和致突变性。
