地塞米松的诱导效应对异烟肼大鼠肝毒性的影响  

Exacerbating effects of dexamethasone on isoniazid-induced hepatotoxicity in rats

作　　者：王来友[1] 陈玲燕[2] 程宝[1] 毕惠嫦[2] 胡因铭[1] 

机构地区：[1]广东药学院中医药研究院,广东广州510006 [2]中山大学临床药理研究所,广东广州510006

出　　处：《中国药理学通报》2013年第7期947-951,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金青年基金资助项目(No 81102502);教部留学回国人员科研启动基金

摘　　要：目的观察大鼠孕烷X受体(pregnane X receptor,PXR)激活剂地塞米松(dexamethasone,DEX)对异烟肼(isoniazid,INH)肝毒性的影响,探讨其发生机制,为临床上抗结核药物所致肝损伤的防治策略提供理论依据。方法 SD♂大鼠随机分成4组(n=6):对照组、INH给药组、DEX给药组和INH-DEX合并给药组,分别给予含DEX 20 mg.kg-1的饲料和含1 000 mg.L-1INH的水喂养28 d后,测定肝脏指数(liver index))和药物代谢酶CYP3A活性,并制备肝组织切片观察各组大鼠肝毒性的程度,同时分析血清中酶学指标ALT、AST、ALP和血脂水平。结果使用DEX组的大鼠肝脏指数与对照组相比明显上升(P<0.01),INH合用DEX后肝细胞CYP3A活性与对照组相比增加了近3.0倍(P<0.01),其肝组织损伤程度加剧,肝细胞脂肪变性并伴有大片梗死,血清中ALT、AST、ALP、血脂水平均较单用INH组明显升高。结论大鼠PXR激活剂DEX能增强INH导致的大鼠肝毒性,其机制可能与DEX上调CYP3A的活性有关。Aim To observe the effects of rat specific PXR activator dexamethasone （DEX） on isoniazid （INH）-induced hepatotoxicity and investigate the mechanism, in order to provide theoretical basis for clinical strategies against anti-tuberculosis drug-in- duced liver injury. Methods Male SD rats were ran- domly divided into four groups （n = 6）：Control, DEX, INH and DEX-INH group. Rats were fed a DEX-containing diet （20 mg kg-1, W/W） and INH-containing water （1000 mg L-1, W/V）respectively. Hepatotoxicity was evaluated 4 weeks after the treat- ment by histological chemistry. The activity of CYP3A in hepatic tissues, the serum ALT, AST, ALP and lip- ids level were determined. Results Rat liver index increased significantly in the groups which were fed di- et containing DEX. CYP3A activity in DEX-INH group increased nearly threefold compared with the control group. The histological detection showed fatty degener-ation and piecemeal necrosis occurred in DEX-INH group. There was a significant difference between INH group and DEX-INH group in the serum ALT, AST, ALP and TC level （ P 〈 0. O1 ）. Conclusion Rat PXR activator DEX can exacerbate INH-induced liver injury. Its mechanism may be related to up-regulation of CYP3A activity by DEX.

关 键 词：肝毒性 药物相互作用 异烟肼 代谢酶 孕烷X受体 抑制剂 

分 类 号：R-332[医药卫生] R322.47