Dahm L J, Roth R A
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Biochem Pharmacol. 1991 Aug 22;42(6):1181-8. doi: 10.1016/0006-2952(91)90252-z.
alpha-Naphthylisothiocyanate (ANIT) injures bile duct epithelium and hepatic parenchymal cells in rats. It is commonly believed that ANIT must undergo bioactivation by hepatic, cytochrome P450-dependent mixed-function oxidases (MFO), since agents which are inducers or inhibitors of hepatic MFO activity enhance or attenuate, respectively, the liver injury associated with ANIT. Several of these agents also affect hepatic glutathione (GSH) content and/or GSH S-transferase activity in a manner to suggest a causal role for GSH in ANIT-induced hepatotoxicity. To determine whether GSH might be involved in the mechanism of injury, buthionine sulfoximine (BSO), diethyl maleate (DEM), or phorone was used to reduce hepatic non-protein sulfhydryl (NPSH) content, an indicator of GSH content. Twenty-four hours after ANIT treatment, rats exhibited cholestasis and elevations in serum of total bilirubin concentration, total bile acid concentration, aspartate aminotransferase (AST) activity, and gamma-glutamyltransferase activity. Cotreatment of rats with BSO decreased NPSH content by 70% at 24 hr and prevented the cholestasis and elevations in serum markers of liver injury caused by ANIT. Likewise, cotreatment of rats with DEM afforded protection against markers of liver injury. Phorone treatment attenuated ANIT-induced elevations in serum total bilirubin concentration and AST activity. Although BSO treatment afforded protection against ANIT-induced liver injury at 24 hr, the injury was evident at 48 hr, and it appeared to coincide with a return of hepatic NPSH content. These results suggest that GSH plays a causal or permissive role in the liver injury caused by ANIT.
α-萘基异硫氰酸酯（ANIT）可损伤大鼠胆管上皮细胞和肝实质细胞。人们普遍认为，ANIT必须经肝脏中细胞色素P450依赖的混合功能氧化酶（MFO）进行生物活化，因为作为肝脏MFO活性诱导剂或抑制剂的药物分别增强或减弱了与ANIT相关的肝损伤。其中几种药物还以某种方式影响肝脏谷胱甘肽（GSH）含量和/或GSH S-转移酶活性，提示GSH在ANIT诱导的肝毒性中起因果作用。为了确定GSH是否可能参与损伤机制，使用丁硫氨酸亚砜胺（BSO）、马来酸二乙酯（DEM）或佛尔酮来降低肝脏非蛋白巯基（NPSH）含量，这是GSH含量的一个指标。ANIT处理24小时后，大鼠出现胆汁淤积，血清总胆红素浓度、总胆汁酸浓度、天冬氨酸转氨酶（AST）活性和γ-谷氨酰转移酶活性升高。用BSO对大鼠进行联合处理在24小时时使NPSH含量降低了70%，并预防了由ANIT引起的胆汁淤积和肝脏损伤血清标志物升高。同样，用DEM对大鼠进行联合处理可提供针对肝脏损伤标志物的保护。佛尔酮处理减弱了ANIT诱导的血清总胆红素浓度和AST活性升高。虽然BSO处理在24小时时对ANIT诱导的肝损伤提供了保护，但在48小时时损伤明显，并且似乎与肝脏NPSH含量的恢复一致。这些结果表明，GSH在ANIT引起的肝损伤中起因果或允许作用。
