Department of Biochemical Toxicology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
J Toxicol Sci. 2011 Oct;36(5):635-43. doi: 10.2131/jts.36.635.
Auranofin, a disease-modifying gold compound, has been empirically applying to the management of rheumatoid arthritis. We investigated a protective effect of auranofin against hepatic injury induced by cocaine. Cocaine (75 mg/kg) markedly increased serum alanine amino transferase (ALT) (4,130 IU/l) and aspartate amino transferase (AST) (1,730 IU/l) activities at 16 hr after treatment, and induced hepatic necrosis surrounding central veins in mice. Concurrently, overexpression of heme oxygenase-1 (HO-1), a rate-limiting enzyme for heme degradation and an oxidative stress marker, was identified at the edges of cocaine-mediated necrotic area. Auranofin (10 mg/ml, i.p.) significantly induced hepatic HO-1 protein in mice from 12 hr after treatment. Interestingly, pretreatment with auranofin resulted in the prevention of the increase of serum ALT and AST activities in a dose-dependent manner. On the other hand, although cocaine increased tumor necrosis factor α (TNFα) gene expression in mouse livers, cocaine-induced liver injury was observed in TNFα deficient mice as well as wild-type mice. Auranofin-inducted HO-1 gene expression was observed in human primary hepatocytes as well as mouse primary hepatocytes. The present findings suggest that auranofin is effective in preventing cocaine-induced hepatic injury, and HO-1 may contribute to protect against chemically-induced cytotoxicity.
金诺芬，一种疾病修饰型的金化合物，已被经验性地应用于类风湿关节炎的治疗。我们研究了金诺芬对可卡因诱导的肝损伤的保护作用。可卡因（75mg/kg）在治疗后 16 小时显著增加血清丙氨酸氨基转移酶（ALT）（4130IU/L）和天冬氨酸氨基转移酶（AST）（1730IU/L）的活性，并诱导小鼠肝中央静脉周围发生坏死。同时，在可卡因介导的坏死区域边缘，鉴定到血红素加氧酶-1（HO-1）的过表达，HO-1 是血红素降解的限速酶，也是氧化应激的标志物。金诺芬（10mg/ml，腹腔注射）从治疗后 12 小时起明显诱导小鼠肝 HO-1 蛋白的表达。有趣的是，金诺芬预处理以剂量依赖的方式防止血清 ALT 和 AST 活性的增加。另一方面，尽管可卡因增加了小鼠肝脏中肿瘤坏死因子 α（TNFα）基因的表达，但在 TNFα 缺陷型小鼠和野生型小鼠中也观察到可卡因诱导的肝损伤。在人原代肝细胞和小鼠原代肝细胞中均观察到金诺芬诱导的 HO-1 基因表达。这些发现表明，金诺芬可有效预防可卡因诱导的肝损伤，HO-1 可能有助于对抗化学诱导的细胞毒性。
