Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats
Diclofenac acyl glucuronide, a major biliary metabolite, is directly involved in small intestinal injury in rats
复制标题
DOI：
10.1016/s0016-5085(98)70026-5
复制
发表时间：
1998-12-01
期刊：
影响因子：
29.4
通讯作者：
Boelsterli, UA
中科院分区：
文献类型：
--
作者：
Seitz, S;Boelsterli, UA
背景和目标：非甾体抗炎药的肠肝再循环是肠损伤发病机制中的一个关键因素，但其潜在的毒性机制仍不清楚。本研究的目的是检查双氯芬酸酰基葡糖苷酸（主要胆汁代谢产物，具有化学反应性）在小肠溃疡形成中的作用。研究方法：使用肝管结合物输出泵缺陷（TR-）大鼠选择性阻断双氯芬酸肠肝循环，而不中断胆汁流动。将双氯芬酸处理的正常大鼠胆汁经口转移至野生型和TR-大鼠，并将溃疡形成程度与含游离双氯芬酸的对照胆汁诱导的溃疡形成程度进行比较。还测定了诱导肝双氯芬酸葡萄糖醛酸转移酶对双氯芬酸诱导溃疡严重程度的影响。结果：TR-大鼠对双氯芬酸无论是经口还是腹腔给药均无反应.然而，转移含有双氯芬酸葡萄糖醛酸苷的胆汁显着增加了正常和TR大鼠溃疡形成的程度。此外，葡萄糖醛酸转移酶的诱导加重肠溃疡。结论：双氯芬酸的反应性酰基葡糖苷酸或其氧化代谢产物之一的酰基葡糖苷酸直接参与小肠损伤的发病机制。
Background & Aims: Enterohepatic recirculation of nonsteroidal anti-inflammatory drugs is a critical factor in the pathogenesis of intestinal injury, but the underlying mechanism of toxicity remains obscure. The aim of this study was to examine the role of diclofenac acyl glucuronide, which is the major biliary metabolite and is chemically reactive, in the precipitation of small intestinal ulceration. Methods: Hepatocanalicular conjugate export pump-deficient (TR-) rats were used to selectively block diclofenac enterohepatic circulation without interrupting bile flow. Bile from diclofenac-treated normal rats was orally transferred to wild-type and TR- rats, and the extent of ulcer formation was compared with that induced by control bile containing free diclofenac. The effect of induction of hepatic diclofenac glucuronosyltransferase on the severity of diclofenac-induced ulceration was also determined. Results: TR- rats were refractory to diclofenac given either intraperitoneally or perorally. However, transfer of bile containing diclofenac glucuronide significantly increased the extent of ulcer formation in both normal and TR- rats. Moreover, induction of glucuronosyltransferase aggravated intestinal ulceration. Conclusions: The reactive acyl glucuronide of diclofenac, or the acyl glucuronide of one of its oxidative metabolites, is directly involved in the pathogenesis of small intestinal injury.