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Protection from drug-induced hepatocellular changes by pretreatment with conjugating enzyme inhibitors in rats

机译：结合酶抑制剂预处理可预防药物诱导的肝细胞变化

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The present paper describes the role of conjugating enzymes in the development of hepatotoxicity after administration of repeated doses of a novel monoamine oxidase type-A (MAO-A) inhibitor, (5R)3-[2-(1S)-3-cyano-1 -hydroxypropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinine (E2011). The effects of pretreatment with three kinds of conjugating enzyme inhibitors on hepatic lesions induced by E2011 were evaluated in female Sprague-Dawley rats. The inhibitors used were 2,6-dichloro-4-nitrophenol (DCNP; inhibitor of sulfotransferase (ST)), pentachlorophenol (PCP; inhibitor of both ST and acetyltransferase (AT) or ranitidine (inhibitor of UDP-glucuronosyltransferase (UDP-GT)). Two weeks treatment of E2011 alone at an oral dosage of 150 mg/kg induced hepatocellular changes characterized by nuclear enlargement. Daily pretreatment with DCNP (10 mg/kg, i.p.) enhanced the E2011-induced hepatocellular changes accompanied by single cell necrosis. On the other hand, the hepatotoxicity was clearly diminished by PCP (5 mg/kg, i.p.). Ranitidine pretreatment had no effect. Protection by PCP was attributed to the inhibitory effects of AT in addition to ST; it was considered that the hepatocellular changes caused by E2011 were largely dependent on the formation of acetyl conjugate(s), (C) 2001 Elsevier Science Inc. All rights reserved. [References: 20]
机译：本论文描述了重复给药新型单胺氧化酶A型（MAO-A）抑制剂（5R）3- [2-（1S）-3-cyano-后，共轭酶在肝毒性发展中的作用。 1-羟丙基）苯并噻唑-6-基] -5-甲氧基甲基-2-恶唑烷（E2011）。在雌性Sprague-Dawley大鼠中评估了三种共轭酶抑制剂预处理对E2011诱导的肝损伤的影响。使用的抑制剂是2,6-二氯-4-硝基苯酚（DCNP;磺基转移酶（ST）抑制剂），五氯苯酚（PCP; ST和乙酰基转移酶（AT）或雷尼替丁的抑制剂（UDP-葡萄糖醛糖基转移酶（UDP-GT）的抑制剂） ）。口服剂量为150 mg / kg的E2011单独治疗两周后会诱发以核扩大为特征的肝细胞变化，每天用DCNP（10 mg / kg，ip）预处理可增强E2011诱导的肝细胞变化并伴有单细胞坏死。另一方面，五氯苯酚（5 mg / kg，腹膜内）明显降低了肝毒性，雷尼替丁预处理没有作用，五氯苯酚的保护作用归因于除ST外还具有AT的抑制作用;认为是肝细胞的变化。由E2011引起的代谢产物很大程度上取决于乙酰基缀合物的形成，（C）2001 Elsevier Science Inc.保留所有权利[参考文献：20]

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