Fitzsimmons M E, Anders M W
Department of Pharmacology, University of Rochester School of Medicine & Dentistry, New York 14642.
Chem Res Toxicol. 1993 Sep-Oct;6(5):662-8. doi: 10.1021/tx00035a011.
5,6-Dichloro-4-thia-5-hexenoic acid (DCTH), the desamino analog of the nephrotoxic cysteine S-conjugate S-(1,2-dichlorovinyl)-L-cysteine, is toxic to liver and kidney mitochondria. The mechanism by which DCTH produces mitochondrial dysfunction has not been defined. The objective of the present experiments was to test the hypothesis that DCTH is bioactivated by the mitochondrial fatty acid beta-oxidation system to cytotoxic intermediates. Incubation of isolated rat hepatocytes with DCTH produced a time- and concentration-dependent decrease in cell viability. The even-chain, elongated analog 7,8-dichloro-6-thia-7-octenoic acid was also cytotoxic, whereas the odd-chain-length analogs 6,7-dichloro-5-thia-6-heptenoic acid and 8,9-dichloro-7-thia-8-nonenoic acid were not. Sodium benzoate reduced the cytotoxicity of DCTH, indicating a role for coenzyme A in the bioactivation of DCTH. DCTH decreased cellular ATP concentrations, the cellular energy charge, and cellular glutathione concentrations; these changes preceded the decrease in cell viability, indicating that mitochondrial dysfunction may be an early event in DCTH-induced cytotoxicity. 6-Chloro-5,5,6-trifluoro-4-thiahexanoic acid and 5,6,7,8,8-pentachloro-4-thia-5,7-octadienoic acid were also cytotoxic in isolated hepatocytes, whereas 4-(2-benzothiazolyl)-4-thiabutanoic acid was not. These data are consistent with the hypothesis that the mitochondrial fatty acid beta-oxidation system is involved in the bioactivation of DCTH and that mitochondria may be important cellular targets in DCTH-induced cytotoxicity.
5,6-二氯-4-硫杂-5-己烯酸（DCTH）是具有肾毒性的半胱氨酸S-结合物S-(1,2-二氯乙烯基)-L-半胱氨酸的脱氨基类似物，对肝脏和肾脏线粒体具有毒性。DCTH产生线粒体功能障碍的机制尚未明确。本实验的目的是检验以下假设：DCTH通过线粒体脂肪酸β-氧化系统生物活化成细胞毒性中间体。用DCTH孵育分离的大鼠肝细胞会导致细胞活力呈时间和浓度依赖性下降。偶数链、延长型类似物7,8-二氯-6-硫杂-7-辛烯酸也具有细胞毒性，而奇数链长度类似物6,7-二氯-5-硫杂-6-庚烯酸和8,9-二氯-7-硫杂-8-壬烯酸则不具有细胞毒性。苯甲酸钠降低了DCTH的细胞毒性，表明辅酶A在DCTH的生物活化中起作用。DCTH降低了细胞内ATP浓度、细胞能量负荷和细胞谷胱甘肽浓度；这些变化在细胞活力下降之前出现，表明线粒体功能障碍可能是DCTH诱导细胞毒性的早期事件。6-氯-5,5,6-三氟-4-硫杂己酸和5,6,7,8,8-五氯-4-硫杂-5,7-辛二烯酸在分离的肝细胞中也具有细胞毒性，而4-(2-苯并噻唑基)-4-硫杂丁酸则不具有细胞毒性。这些数据与以下假设一致：线粒体脂肪酸β-氧化系统参与DCTH的生物活化，并且线粒体可能是DCTH诱导细胞毒性的重要细胞靶点。
