Luu N C, Iyer R A, Anders M W, Ridge D P
Department of Chemistry and Biochemistry, University of Delaware, Newark 19716, USA.
Chem Res Toxicol. 2000 Jul;13(7):610-5. doi: 10.1021/tx990179v.
Glutathione conjugate formation plays important roles in the detoxification and bioactivation of xenobiotics. A range of nephrotoxic haloalkenes undergo bioactivation that involves glutathione and cysteine S-conjugate formation. The cysteine S-conjugates thus formed may undergo cysteine conjugate beta-lyase-catalyzed biotransformation to form cytotoxic thiolates or thiiranes. In the studies presented here, cysteine conjugate beta-lyase-catalyzed biotransformations were modeled by anion-induced elimination reactions of S-(2-bromo-1,1, 2-trifluoroethyl)-N-acetyl-L-cysteine methyl ester, S-(2-chloro-1,1, 2-trifluoroethyl)-N-acetyl-L-cysteine methyl ester, and S-(2-fluoro-1,1,2-trifluoroethyl)-N-acetyl-L-cysteine methyl ester in the gas phase. Examination of these processes in the gas phase allowed direct observation of the formation of cysteine S-conjugate-derived thiolates and thiiranes, whose formation is inferred from condensed-phase results. The cysteine S-conjugates of these haloethenes exhibit distinctive patterns of mutagenicity that are thought to be correlated with the nature of the products formed by their cysteine conjugate beta-lyase-catalyzed biotransformation. In particular, S-(2-bromo-1,1,2-trifluoroethyl)-L-cysteine is mutagenic, whereas the chloro and fluoro analogues are not. It has been proposed that the mutagenicity of S-(2-bromo-1,1, 2-trifluoroethyl)-L-cysteine is correlated with the greater propensity of the bromine-containing cysteine S-conjugate to form a thiirane compared with those of the chlorine- or fluorine-containing conjugates. The ease of thiirane formation is consistent with the gas-phase results presented here, which show that the bromine-containing conjugate has a greater propensity to form a thiirane on anionic base-induced elimination than the chloro- or fluoro-substituted analogues. The blocked cysteine S-conjugates were deprotonated by gas-phase ion-molecule reactions with hydroxide, methoxide, and ethoxide ions and then allowed to decompose. The mechanisms for these decompositions are discussed as well as the insights into the bioactivation of these cysteine S-conjugates provided by the further decompositions of thiolate intermediates.
谷胱甘肽共轭物的形成在异生物素的解毒和生物活化过程中起着重要作用。一系列具有肾毒性的卤代烯烃会发生生物活化，这涉及谷胱甘肽和半胱氨酸S-共轭物的形成。如此形成的半胱氨酸S-共轭物可能会经历半胱氨酸共轭β-裂解酶催化的生物转化，形成具有细胞毒性的硫醇盐或硫杂环丙烷。在本文所展示的研究中，通过S-(2-溴-1,1,2-三氟乙基)-N-乙酰-L-半胱氨酸甲酯、S-(2-氯-1,1,2-三氟乙基)-N-乙酰-L-半胱氨酸甲酯和S-(2-氟-1,1,2-三氟乙基)-N-乙酰-L-半胱氨酸甲酯在气相中的阴离子诱导消除反应，对半胱氨酸共轭β-裂解酶催化的生物转化进行了模拟。在气相中对这些过程的研究使得能够直接观察到半胱氨酸S-共轭物衍生的硫醇盐和硫杂环丙烷的形成，其形成是从凝聚相结果推断出来的。这些卤代乙烯的半胱氨酸S-共轭物表现出独特的致突变模式，据认为这与它们通过半胱氨酸共轭β-裂解酶催化的生物转化所形成的产物的性质相关。特别地，S-(2-溴-1,1,2-三氟乙基)-L-半胱氨酸具有致突变性，而氯代和氟代类似物则没有。有人提出，S-(2-溴-1,1,2-三氟乙基)-L-半胱氨酸的致突变性与含溴半胱氨酸S-共轭物相比含氯或含氟共轭物更倾向于形成硫杂环丙烷有关。硫杂环丙烷形成的难易程度与本文所展示的气相结果一致，该结果表明，与氯代或氟代取代的类似物相比，含溴共轭物在阴离子碱诱导消除时更倾向于形成硫杂环丙烷。通过与氢氧根离子、甲氧基离子和乙氧基离子的气相离子-分子反应，使封闭的半胱氨酸S-共轭物去质子化，然后使其分解。讨论了这些分解的机制以及硫醇盐中间体的进一步分解为这些半胱氨酸S-共轭物的生物活化提供的见解。
