BROMOBENZENE-INDUCED LIVER NECROSIS - PROTECTIVE ROLE OF GLUTATHIONE AND EVIDENCE FOR 3,4-BROMOBENZENE OXIDE AS HEPATOTOXIC METABOLITE
BROMOBENZENE-INDUCED LIVER NECROSIS - PROTECTIVE ROLE OF GLUTATHIONE AND EVIDENCE FOR 3,4-BROMOBENZENE OXIDE AS HEPATOTOXIC METABOLITE
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DOI：
10.1159/000136485
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发表时间：
1974-01-01
期刊：
影响因子：
3.1
通讯作者：
GILLETTE, JR
中科院分区：
文献类型：
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作者：
JOLLOW, DJ;MITCHELL, JR;GILLETTE, JR
该实验室先前假设，溴苯诱导的肝坏死是由一种活性代谢物的形成引起的，这种代谢物使重要的细胞大分子芳基化。因此，在各种改变肝毒性的预处理方案后，肝坏死的严重程度与溴苯代谢物的形成和体外代谢产物的共价结合进行了比较。这些数据提供了直接的动力学证据，证明3,4-溴苯氧化物是反应性肝毒性代谢物。研究还表明，肝毒性代谢物优先与谷胱甘肽结合（解毒），从而从肝脏中消耗谷胱甘肽。肝坏死和细胞大分子芳基化仅在谷胱甘肽不再可用时发生。因此，溴苯引起的肝坏死存在剂量阈值。
This laboratory has previously postulated that bromobenzene-induced hepatic necrosis results from the formation of a reactive metabolite that arylates vital cellular macromolecules. Accordingly, the severity of liver necrosis has been compared with the formation of metabolites of bromobenzene and with covalent binding of metabolitesin vivoandin vitroafter various pretreatment regimens that alter hepatotoxicity. These data provide direct kinetic evidence that 3,4-bromobenzene oxide is the reactive hepatotoxic metabolite. The studies also demonstrate that the hepatotoxic metabolite is preferentially conjugated (detoxified) with glutathione, thereby depleting glutathione from the liver. Liver necrosis and arylation of cellular macromolecules occur only when glutathione is no longer available. Thus, a dose threshold exists for bromobenzene-induced hepatic necrosis.