DILI frequently contributes to the attrition of new drug candidates and is a common cause for the withdrawal of approved drugs from the market. Although some noncytochrome P450 (non-CYP) metabolism enzymes have been implicated in DILI development, their association with DILI outcomes has not been systematically evaluated. In this study, we analyzed a large data set comprising 317 drugs and their interactions in vitro with 42 non-CYP enzymes as substrates, inducers, and/or inhibitors retrieved from historical regulatory documents. We examined how these in vitro drug-enzyme interactions are correlated with the drugs’ potential for DILI concern, as classified in the Liver Toxicity Knowledge Base database. Our study revealed that drugs that inhibit non-CYP enzymes are significantly associated with high DILI concern. Particularly, interaction with UDP-glucuronosyltransferases (UGT) enzymes is an important predictor of DILI outcomes. Further analysis indicated that only pure UGT inhibitors and dual substrate inhibitors, but not pure UGT substrates, are significantly associated with high DILI concern. Notably, drug interactions with UGT enzymes may independently predict DILI, and their combined use with the rule-of-two model further improves overall predictive performance. These findings could expand the currently available tools for assessing the potential for DILI in humans.

中文翻译：

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药物与 Udp-葡萄糖醛酸转移酶 (UGT) 的相互作用是药物性肝损伤的预测因子


DILI 经常导致新候选药物的流失，也是已批准药物退出市场的常见原因。尽管一些非细胞色素 P450 (non-CYP) 代谢酶与 DILI 的发生有关，但它们与 DILI 结果的关联尚未得到系统评估。在这项研究中，我们分析了一个包含 317 种药物及其与 42 种非 CYP 酶作为底物、诱导剂和/或抑制剂的体外相互作用的大型数据集，这些药物从历史监管文件中检索。我们研究了这些体外药物-酶相互作用如何与药物潜在的 DILI 相关（如肝脏毒性知识库数据库中的分类）。我们的研究表明，抑制非 CYP 酶的药物与高 DILI 关注度显着相关。特别是，与 UDP-葡萄糖醛酸基转移酶 (UGT) 的相互作用是 DILI 结果的重要预测因子。进一步分析表明，只有纯 UGT 抑制剂和双底物抑制剂与高 DILI 关注度显着相关，而纯 UGT 底物则不然。值得注意的是，药物与 UGT 酶的相互作用可以独立预测 DILI，并且它们与二法则模型的结合使用进一步提高了整体预测性能。这些发现可以扩展目前用于评估人类 DILI 潜力的可用工具。