Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Konohanaku, Osaka, Japan.
Regul Toxicol Pharmacol. 2011 Aug;60(3):323-31. doi: 10.1016/j.yrtph.2011.04.009. Epub 2011 May 7.
Antiepileptic agents are known to cause adverse effects in human liver, including steatosis. Clobazam (CLB), a 1,5-benzodiazepine, is clinically used as an antiepileptic agent. In the previous study, 4-week treatment with CLB induced hepatomegaly in male rats. In the present study, the human risk of hepatomegaly was assessed and the causative mechanism in terms of cell proliferation and apoptosis, oxidative stress, and drug-metabolizing enzyme induction was elucidated by toxicological approach. Male SD rats were treated orally with 400 mg/kg CLB for 1, 3, 7, 14, or 28 days. The 28-day treatment was followed by 7 or 14 days of withdrawal. At the end of each treatment, the liver and plasma of each rat were examined. Liver weight increased from Day 3 of CLB treatment. This increase was mostly accompanied by hepatic centrilobular hypertrophy and proliferation of smooth endoplasmic reticulum (SER), and by an increase in microsomal proteins. Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 mRNA levels in the liver were upregulated as compared to the control group throughout the dosing period. On the other hand, the thiobarbituric acid reactive substance (TBARS) formulation, hepatocyte proliferation, and apoptosis, assumed to play roles in laying groundwork for effective induction of metabolizing enzymes, were increased only at the acute phase of treatment. These results suggested that CLB-induced hepatomegaly in male rats is mainly attributable to microsomal enzyme induction associated with Cyp2b1, Cyp3a1, Cyp3a2, and Ugt2b2 gene upregulation, but does not cause any toxicological concerns.
抗癫痫药物已知会对人类肝脏造成不良反应，包括脂肪变性。氯巴占（CLB），一种 1,5-苯二氮䓬，临床上用作抗癫痫药物。在之前的研究中，4 周的 CLB 治疗导致雄性大鼠肝肿大。在本研究中，通过毒理学方法评估了 CLB 导致人类肝肿大的风险，并阐明了细胞增殖和凋亡、氧化应激和药物代谢酶诱导方面的致病机制。雄性 SD 大鼠经口给予 400mg/kg CLB 治疗 1、3、7、14 或 28 天。28 天治疗后停药 7 或 14 天。在每个治疗周期结束时，检查每组大鼠的肝脏和血浆。CLB 治疗第 3 天开始，肝脏重量增加。这种增加主要伴随着肝中央小叶肥大和光滑内质网（SER）增殖，以及微粒体蛋白增加。与对照组相比，整个给药期内，肝 Cyp2b1、Cyp3a1、Cyp3a2 和 Ugt2b2mRNA 水平上调。另一方面，丙二醛（TBARS）形成、肝细胞增殖和凋亡，被认为在有效诱导代谢酶的形成中发挥作用，仅在治疗的急性期增加。这些结果表明，CLB 诱导雄性大鼠肝肿大主要归因于与 Cyp2b1、Cyp3a1、Cyp3a2 和 Ugt2b2 基因上调相关的微粒体酶诱导，但不会引起任何毒理学问题。
