三乙酰竹桃霉素（一种CYP3A的特异性抑制剂）对乙醇介导的对乙酰氨基酚肝毒性的保护作用

Protection of ethanol-mediated acetaminophen hepatotoxicity by triacetyloleandomycin, a specific inhibitor of CYP3A.

作者信息

Kostrubsky V E, Szakacs J G, Jeffery E H, Woods S G, Bement W J, Wrighton S A, Sinclair P R, Sinclair J F

机构信息

Veterans Administration Medical Center, White River Junction, VT 05009, USA.

出版信息

Ann Clin Lab Sci. 1997 Jan-Feb;27(1):57-62.

PMID:8997458

Abstract

Cytochrome P450 2E (CYP2E) is considered responsible for ethanol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, it has been shown in cultured human and rat hepatocytes and intact rats that ethanol induces CYP3A in addition to CYP2E. Therefore, an investigation was made in rats to see whether or not an inhibitor of CYP3A, triacetyloleandomycin (TAO), would protect against ethanol-mediated increases in APAP hepatotoxicity. Rats, treated with 6.3 percent ethanol in the Lieber-DeCarli diet for 7 days, were administered APAP (lg/kg, i.g.) 11 hrs after removal of the diet. Triacetyloleandomycin (500 mg/kg, saline solution) was injected i.p. 2 hrs before the administration of APAP. In rats pretreated with ethanol, treatment with APAP for 7 hrs resulted in focal centrilobular congestion and steatosis. Triacetyloleandomycin completely prevented the histological liver damage in all 8 animals. These results suggest that, in ethanol-treated rats, CYP3A plays a major role in increasing APAP hepatotoxicity.

摘要

细胞色素P450 2E（CYP2E）被认为是乙醇介导的对乙酰氨基酚（APAP）肝毒性增加的原因。然而，在培养的人和大鼠肝细胞以及完整大鼠中已表明，乙醇除了诱导CYP2E外，还会诱导CYP3A。因此，在大鼠中进行了一项研究，以观察CYP3A抑制剂三乙酰竹桃霉素（TAO）是否能预防乙醇介导的APAP肝毒性增加。用含6.3%乙醇的Lieber-DeCarli饮食喂养7天的大鼠，在去除饮食11小时后给予APAP（1g/kg，腹腔注射）。在给予APAP前2小时腹腔注射三乙酰竹桃霉素（500mg/kg，生理盐水溶液）。在用乙醇预处理的大鼠中，用APAP处理7小时导致局灶性小叶中央充血和脂肪变性。三乙酰竹桃霉素完全预防了所有8只动物的肝脏组织学损伤。这些结果表明，在乙醇处理的大鼠中，CYP3A在增加APAP肝毒性方面起主要作用。