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Cytochrome P450 3A4-Mediated Bioactivation and Its Role in Nomilin-Induced Hepatotoxicity.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-07-07 , DOI: 10.1021/acs.chemrestox.0c00228 Lei Zhang 1 , Qingwang Liu 2 , Yajuan Pan 3 , Xianfang Qi 1 , Yuanlong Li 1 , Ci Chen 1 , Jun Sun 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2020-07-07 , DOI: 10.1021/acs.chemrestox.0c00228 Lei Zhang 1 , Qingwang Liu 2 , Yajuan Pan 3 , Xianfang Qi 1 , Yuanlong Li 1 , Ci Chen 1 , Jun Sun 1
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Nomilin is a furan-containing triterpenoid isolated from the medicinal plants of citrus. The aim of this study was to investigate the in vitro and in vivo bioactivation of nomilin and the role in nomilin-induced hepatotoxicity. Microsomal incubations of nomilin supplemented with NADPH and GSH or NAL resulted in the detection of six conjugates (M1–M6). The structures of the metabolites were characterized based on LC-HRMS and NMR. Nomilin was bioactivated to a reactive cis-butene-dial (BDA) intermediate dependent on NADPH, and this intermediate suffered from the reaction with the nucleophiles (GSH and NAL) to form stable adducts. M1–M4 were identified as pyrrole derivatives, and M5 and M6 were pyrrolinone derivatives. M1 was further chemically synthesized and characterized by 13C NMR spectroscopy. M1 was the major metabolite detected in mice bile. Pretreatment with ketoconazole significantly reduced the formation of M1 in mice bile, while pretreatment with rifampicin significantly increased the formation of M1. Chemical inhibition together with recombinant human CYP450 phenotyping demonstrated that CYP3A4 was the major enzyme contributing to the bioactivation of nomilin. Toxicity study suggested that nomilin displayed dose-dependent liver injury in mice, while tetrahydro-nomilin was found to be nonhepatotoxic. Pretreatment with ketoconazole prevented mice from nomilin-induced liver injury. The liver injury induced by nomilin was deteriorated when the mice were pretreated with rifampicin. These findings provide evidence that CYP3A4-mediated bioactivation was indispensable in nomilin-induced hepatotoxicity.
中文翻译：
细胞色素 P450 3A4 介导的生物活化及其在诺米林诱导的肝毒性中的作用。
Nomilin 是一种从柑橘类药用植物中分离出来的含呋喃的三萜类化合物。本研究的目的是研究诺米林的体外和体内生物活性以及在诺米林诱导的肝毒性中的作用。用 NADPH 和 GSH 或 NAL 补充诺米林的微粒体孵育导致检测到六种偶联物 (M1-M6)。基于LC-HRMS和NMR表征代谢物的结构。Nomilin 被生物活化为活性顺式丁烯二醛 (BDA) 中间体依赖于 NADPH，该中间体与亲核试剂（GSH 和 NAL）反应形成稳定的加合物。M1-M4被鉴定为吡咯衍生物，M5和M6是吡咯啉酮衍生物。M1 进一步化学合成并表征为13C 核磁共振光谱。M1 是在小鼠胆汁中检测到的主要代谢物。酮康唑预处理显着减少小鼠胆汁中 M1 的形成，而利福平预处理显着增加 M1 的形成。化学抑制连同重组人 CYP450 表型表明 CYP3A4 是有助于诺米林生物活化的主要酶。毒性研究表明诺米林在小鼠中表现出剂量依赖性肝损伤，而四氢诺米林被发现无肝毒性。用酮康唑预处理可防止小鼠免于诺米林引起的肝损伤。当小鼠用利福平预处理时，诺米林引起的肝损伤恶化。这些发现提供了证据，证明 CYP3A4 介导的生物活化在诺米林诱导的肝毒性中是必不可少的。
更新日期：2020-08-17
中文翻译：
细胞色素 P450 3A4 介导的生物活化及其在诺米林诱导的肝毒性中的作用。
Nomilin 是一种从柑橘类药用植物中分离出来的含呋喃的三萜类化合物。本研究的目的是研究诺米林的体外和体内生物活性以及在诺米林诱导的肝毒性中的作用。用 NADPH 和 GSH 或 NAL 补充诺米林的微粒体孵育导致检测到六种偶联物 (M1-M6)。基于LC-HRMS和NMR表征代谢物的结构。Nomilin 被生物活化为活性顺式丁烯二醛 (BDA) 中间体依赖于 NADPH，该中间体与亲核试剂（GSH 和 NAL）反应形成稳定的加合物。M1-M4被鉴定为吡咯衍生物，M5和M6是吡咯啉酮衍生物。M1 进一步化学合成并表征为13C 核磁共振光谱。M1 是在小鼠胆汁中检测到的主要代谢物。酮康唑预处理显着减少小鼠胆汁中 M1 的形成，而利福平预处理显着增加 M1 的形成。化学抑制连同重组人 CYP450 表型表明 CYP3A4 是有助于诺米林生物活化的主要酶。毒性研究表明诺米林在小鼠中表现出剂量依赖性肝损伤，而四氢诺米林被发现无肝毒性。用酮康唑预处理可防止小鼠免于诺米林引起的肝损伤。当小鼠用利福平预处理时，诺米林引起的肝损伤恶化。这些发现提供了证据，证明 CYP3A4 介导的生物活化在诺米林诱导的肝毒性中是必不可少的。
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