Groves C E, Hayden P J, Lock E A, Schnellmann R G
Department of Physiology, College of Medicine, University of Arizona, Tucson 85724.
J Biochem Toxicol. 1993 Mar;8(1):49-56. doi: 10.1002/jbt.2570080108.
The relationship between the covalent binding, uptake, and toxicity produced by S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC) was investigated in suspensions of rabbit renal proximal tubules (RPT). The DCVC and TFEC at concentrations of 25 microM produced a time-dependent (1-6 hours) loss of RPT viability. The TFEC was biotransformed rapidly by beta-lyase to a reactive metabolite which bound covalently to tubular protein. Approximately 63% of the TFEC-equivalents inside the cell were bound to protein. Covalent binding of TFEC-equivalents was associated with a 30% decrease in tubular basal and state 3 respiration, a sevenfold increase in lipid peroxidation, and, ultimately, cell death. The DCVC was biotransformed rapidly to a reactive metabolite which bound covalently to tubular protein. Approximately 90% of the DCVC-equivalents inside the cell were bound covalently to tubular protein. Following exposure to 25 microM DCVC, the binding of DCVC-equivalents was associated with a 17-fold increase in lipid peroxidation but, in contrast to TFEC, had no effect on tubular respiration. However, exposure of RPT to 100 microM DCVC resulted in a ninefold increase in the binding of DCVC-equivalents and a 30% decrease in tubular state 3 respiration. The beta-lyase inhibitor aminooxyacetic acid (AOAA) blocked the covalent binding, mitochondrial dysfunction, lipid peroxidation, and cell death produced by TFEC. The AOAA decreased the covalent binding and the lipid peroxidation produced by DCVC by approximately 60-70% but had no effect on cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
研究了S-(1,2-二氯乙烯基)-L-半胱氨酸(DCVC)和S-(1,1,2,2-四氟乙基)-L-半胱氨酸(TFEC)产生的共价结合、摄取及其毒性之间的关系，实验对象为兔肾近端小管(RPT)悬浮液。浓度为25微摩尔的DCVC和TFEC会导致RPT活力随时间(1至6小时)下降。TFEC被β-裂解酶迅速生物转化为一种活性代谢产物，该产物与肾小管蛋白共价结合。细胞内约63%的TFEC当量与蛋白质结合。TFEC当量的共价结合与肾小管基础呼吸和状态3呼吸下降30%、脂质过氧化增加7倍以及最终细胞死亡有关。DCVC迅速生物转化为一种活性代谢产物，该产物与肾小管蛋白共价结合。细胞内约90%的DCVC当量与肾小管蛋白共价结合。暴露于25微摩尔DCVC后，DCVC当量的结合与脂质过氧化增加17倍有关，但与TFEC不同的是，对肾小管呼吸没有影响。然而，将RPT暴露于100微摩尔DCVC会导致DCVC当量的结合增加9倍，肾小管状态3呼吸下降30%。β-裂解酶抑制剂氨基氧乙酸(AOAA)可阻断TFEC产生的共价结合、线粒体功能障碍、脂质过氧化和细胞死亡。AOAA使DCVC产生的共价结合和脂质过氧化减少约60 - 70%，但对细胞死亡没有影响。(摘要截短于250字)
