Inhibition of ethanol-induced liver disease in the intragastric feeding rat model by chlormethiazole.

Z. Gouillon, D. Lucas, J. Li, A. Hagbjork, B. A. French, P. Fu, C. Fang, M. Ingelman-Sundberg, T. Donohue, S. French
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引用次数: 120

Abstract

The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease. Chlormethiazole has been used in the treatment of alcoholic withdrawal and has been shown to inhibit cytochrome P4502E1. Since treatment of experimental alcoholic liver disease with CYP2E1 inhibitors had an ameliorating effect on liver injury in the rat, chlormethiazole was used to see if it had a similar effect. Rats fed ethanol for 2 months had significantly less liver injury when chlormethiazole was added to the diet, fed intragastrically. The CYP2E1 apoprotein levels, which were increased by ethanol feeding, were also increased when chlormethiazole was fed with ethanol. Chlormethiazole inhibited the increase in the ethanol-induced CYP2E1 activity in vivo, as measured by chlorzoxazone 6-hydroxylation, but did not affect the level of CYP2E1 apoprotein. Likewise, the reduction in proteasome proteolytic enzyme activity produced by ethanol feeding was blunted in chlormethiazole-fed rats. These results support the conclusion that chlormethiazole treatment partially protects the liver from injury by inhibiting CYP2E1 activity in vivo.
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氯甲唑对灌胃大鼠酒精性肝病的抑制作用。
本研究旨在探讨氯甲唑对酒精性肝病大鼠灌胃乙醇喂养模型肝损伤的影响。氯甲基唑已被用于治疗酒精戒断,并已被证明可抑制细胞色素P4502E1。由于用CYP2E1抑制剂治疗实验性酒精性肝病对大鼠肝损伤有改善作用,所以我们使用氯甲基唑来观察它是否有类似的效果。饲喂乙醇2个月的大鼠,在饲料中添加氯甲基唑并灌胃,肝损伤明显减轻。与乙醇饲喂相比,氯甲唑的CYP2E1载脂蛋白水平也有所升高。氯代唑酮6-羟基化法测定,氯甲基唑抑制了体内乙醇诱导的CYP2E1活性的增加,但不影响CYP2E1载子蛋白的水平。同样,在氯甲唑喂养的大鼠中,乙醇喂养产生的蛋白酶体蛋白水解酶活性的降低被钝化。这些结果支持了氯甲唑治疗通过抑制体内CYP2E1活性部分保护肝脏损伤的结论。
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