Hepatotoxicity is one of the most common toxicities observed in non-clinical safety studies of drug candidates, and it is important to understand the hepatotoxicity mechanism to assess the risk of drug-induced liver injury in humans. In this study, we investigated the mechanism of hepatotoxicity caused by 2-[2-Methyl-1-(oxan-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole (DSP-0640), a drug candidate that showed hepatotoxicity characterized by centrilobular hypertrophy and vacuolation of hepatocytes in a 4-week oral repeated-dose toxicity study in male rats. In the liver of rats treated with DSP-0640, the expression of aryl hydrocarbon receptor (AHR) target genes, including Cyp1a1, was upregulated. In in vitro reporter assays, however, DSP-0640 showed only minimal AHR-activating potency. Therefore, we investigated the possibility that DSP-0640 indirectly activated AHR by inhibiting the CYP1 enzyme-dependent clearance of endogenous AHR agonists. In in vitro assays, DSP-0640 showed inhibitory effects on both rat and human CYP1A1 and enhanced rat and human AHR-mediated reporter gene expression induced by 6-formylindolo[3,2-b]carbazole, a well-known endogenous AHR agonist. The possible involvement of CYP1A1 inhibition in AHR activation was also demonstrated with other hepatotoxic compounds tacrine and albendazole. These results suggest that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity caused by DSP-0640 and that DSP-0640 might induce hepatotoxicity in humans as well. We propose that CYP1A1 inhibition-mediated AHR activation is a novel mechanism for drug-induced hepatotoxicity.

中文翻译：

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CYP1A1 抑制介导的芳烃受体活化参与药物诱导的肝毒性。

肝毒性是在候选药物的非临床安全性研究中观察到的最常见的毒性之一，了解肝毒性机制对于评估人类药物性肝损伤的风险非常重要。在本研究中，我们研究了由 2-[2-Methyl-1-(oxan-4-yl)-1H-benzimidazol-5-yl]-1,3-benzoxazole (DSP-0640) 引起的肝毒性机制。在对雄性大鼠进行的为期 4 周的口服重复给药毒性研究中，该候选药物显示出以小叶中心肥大和肝细胞空泡形成为特征的肝毒性。在用 DSP-0640 治疗的大鼠肝脏中，芳烃受体 (AHR) 靶基因（包括 Cyp1a1）的表达上调。然而，在体外报告基因测定中，DSP-0640 仅显示出极小的 AHR 激活效力。所以，我们研究了 DSP-0640 通过抑制内源性 AHR 激动剂的 CYP1 酶依赖性清除间接激活 AHR 的可能性。在体外试验中，DSP-0640 显示出对大鼠和人类 CYP1A1 的抑制作用，并增强了由众所周知的内源性 AHR 激动剂 6-formyllindolo[3,2-b]carbazole 诱导的大鼠和人类 AHR 介导的报告基因表达。其他肝毒性化合物他克林和阿苯达唑也证明了 CYP1A1 抑制可能参与 AHR 激活。这些结果表明 CYP1A1 抑制介导的 AHR 激活与 DSP-0640 引起的肝毒性有关，并且 DSP-0640 也可能在人类中诱导肝毒性。我们提出 CYP1A1 抑制介导的 AHR 激活是药物诱导的肝毒性的新机制。