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-induced liver injury. Methods Male SD rats were randomly 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 treatment 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 diet 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. 01 ). Conclusion Rat PXR activator DEX can exacerbate INH-induced liver injury. Its mechanism may be related to up-regulation of CYP3A activity by DEX.%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-1 INH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.
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