Costa A K, Trudell J R
Department of Anesthesia, Stanford University School of Medicine, California 94305-5117.
Toxicol Appl Pharmacol. 1988 Sep 15;95(2):241-7. doi: 10.1016/0041-008x(88)90160-3.
Hepatic 1,2-dibromoethane (DBE) metabolism proceeds via two pathways: oxidation by cytochrome P-450 and direct conjugation with the ubiquitous tripeptide glutathione (GSH) via the GSH S-transferases. The toxicity of DBE in monolayers of hepatocytes was assessed to establish whether the toxicity of this compound is increased under conditions of reductive metabolism at low oxygen concentrations. Our previous studies with t-butyl hydroperoxide and the calcium ionophore A23187 suggested that hypoxia would exacerbate toxicity that was mediated through lipid peroxidation or loss of calcium homeostasis. Monolayers of hepatocytes were exposed for 2 hr to 0, 14, 140, 1400, or 14,000 ppm of DBE in an atmosphere of either 1, 2, or 20% oxygen. Toxicity was measured by leakage of aspartate aminotransferase (AST) and trypan blue exclusion. The time course of the development of cytotoxicity was examined by assaying cell death both immediately following a 2-hr exposure and 24 hr later. The LC50 of DBE vapor was found to be approximately 14,000 ppm when assayed immediately after exposure but only 140 ppm when assayed 24 hr after exposure. The similarity of the percentages of DBE-induced cell death after incubations at 1, 2, and 20% oxygen demonstrates that the toxicity of DBE is oxygen-independent. We conclude that while DBE is highly toxic to rat hepatocytes, hypoxia does not appear to contribute to the toxicity of DBE, even under conditions of low oxygen concentrations. This result is in direct contrast to a previous report where we showed that the toxicity of halothane is potentiated under hypoxic conditions.
肝脏中1,2 - 二溴乙烷（DBE）的代谢通过两条途径进行：由细胞色素P - 450氧化，以及通过谷胱甘肽S - 转移酶与普遍存在的三肽谷胱甘肽（GSH）直接结合。评估了DBE在肝细胞单层中的毒性，以确定在低氧浓度下的还原代谢条件下该化合物的毒性是否会增加。我们之前使用叔丁基过氧化氢和钙离子载体A23187的研究表明，缺氧会加剧通过脂质过氧化或钙稳态丧失介导的毒性。将肝细胞单层在1%、2%或20%氧气的气氛中暴露于0、14、140、1400或14000 ppm的DBE中2小时。通过天冬氨酸转氨酶（AST）泄漏和台盼蓝排斥法测量毒性。通过在2小时暴露后立即以及24小时后测定细胞死亡来检查细胞毒性发展的时间进程。发现暴露后立即测定时DBE蒸气的半数致死浓度（LC50）约为14000 ppm，但暴露24小时后测定时仅为140 ppm。在1%、2%和20%氧气下孵育后DBE诱导的细胞死亡百分比相似，这表明DBE的毒性与氧气无关。我们得出结论，虽然DBE对大鼠肝细胞具有高毒性，但即使在低氧浓度条件下，缺氧似乎也不会导致DBE的毒性。这一结果与我们之前的一份报告直接相反，在那份报告中我们表明氟烷的毒性在缺氧条件下会增强。
