1,4-二恶烷 (DX) 是一种新兴的水污染物，根据动物研究，被归类为 2B 类肝癌致癌物。了解DX肝脏致癌性的作用机制对于这种环境污染的风险评估和控制具有重要意义。先前的研究表明，小鼠通过饮用水接触高剂量 DX 长达 3 个月会导致肝脏轻度细胞毒性和氧化 DNA 损伤，这一过程与肝脏 CYP2E1 诱导和氧化应激升高相关。为了了解 CYP2E1 在 DX 代谢和肝毒性中的作用，在本研究中，雄性和雌性 Cyp2e1 缺失小鼠暴露于饮用水中的 DX（5000 ppm）1 周或 3 个月。随后对雄性 Cyp2e1 缺失小鼠进行 DX 代谢、氧化还原和分子研究，以与类似处理的雄性野生型 (WT) 和谷胱甘肽 (GSH) 缺陷 Gclm 缺失小鼠进行交叉研究比较。我们的结果表明，两种性别的 Cyp2e1 缺失小鼠均能抵抗 DX 诱导的肝细胞毒性。雄性Cyp2e1缺失小鼠暴露于DX 3个月后，首先，DX代谢为β-羟基乙氧基乙酸降低至WT水平的 ~ 36%；其次，DX诱导的肝脏氧化还原失调（脂质过氧化、GSH氧化和NRF2抗氧化反应的激活）显着减弱；第三，肝脏氧化DNA损伤的水平与DX暴露的WT小鼠相当，并伴有DNA损伤修复反应的抑制；最后，在 DX 暴露的肝脏中没有发现异常增殖或肿瘤前病变。总体而言，这项研究首次揭示，CYP2E1 是高剂量 DX 代谢的主要酶，也是 DX 诱导的肝脏氧化应激和相关细胞毒性的主要贡献者。高剂量 DX 诱导的基因毒性可能通过 CYP2E1 独立途径发生，可能涉及受损的 DNA 损伤修复。© 2024。作者获得 Springer-Verlag GmbH 德国（Springer Nature 旗下公司）的独家许可。

1,4-Dioxane (DX), an emerging water contaminant, is classified as a Group 2B liver carcinogen based on animal studies. Understanding of the mechanisms of action of DX liver carcinogenicity is important for the risk assessment and control of this environmental pollution. Previous studies demonstrate that high-dose DX exposure in mice through drinking water for up to 3 months caused liver mild cytotoxicity and oxidative DNA damage, a process correlating with hepatic CYP2E1 induction and elevated oxidative stress. To access the role of CYP2E1 in DX metabolism and liver toxicity, in the current study, male and female Cyp2e1-null mice were exposed to DX in drinking water (5000 ppm) for 1 week or 3 months. DX metabolism, redox and molecular investigations were subsequently performed on male Cyp2e1-null mice for cross-study comparisons to similarly treated male wildtype (WT) and glutathione (GSH)-deficient Gclm-null mice. Our results show that Cyp2e1-null mice of both genders were resistant to DX-induced hepatocellular cytotoxicity. In male Cyp2e1-null mice exposed to DX for 3 months, firstly, DX metabolism to β-hydroxyethoxyacetic acid was reduced to ~ 36% of WT levels; secondly, DX-induced hepatic redox dysregulation (lipid peroxidation, GSH oxidation, and activation of NRF2 antioxidant response) was substantially attenuated; thirdly, liver oxidative DNA damage was at a comparable level to DX-exposed WT mice, accompanied by suppression of DNA damage repair response; lastly, no aberrant proliferative or preneoplastic lesions were noted in DX-exposed livers. Overall, this study reveals, for the first time, that CYP2E1 is the main enzyme for DX metabolism at high dose and a primary contributor to DX-induced liver oxidative stress and associated cytotoxicity. High dose DX-induced genotoxicity may occur via CYP2E1-independent pathway(s), potentially involving impaired DNA damage repair.© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.