State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, department of biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine , Guangzhou, Guangdong China , 510006.
Mol Pharm. 2017 Sep 5;14(9):2937-2951. doi: 10.1021/acs.molpharmaceut.7b00345. Epub 2017 Jul 17.
Acetaminophen (APAP) is one of the most commonly used oral analgesics and antipyretics, but hepatotoxicity including liver failure may occur after overdose. The therapeutic options for treating APAP hepatotoxicity are limited. Eriodictyol, a dietary flavonoid with anti-inflammatory and antioxidant properties, was used here to determine its protective effects against APAP-induced hepatotoxicity in mice. Various administration routes and pharmacokinetics-pharmacodynamics (PK-PD) analyses were used to determine these effects. Protective effects were observed in intravenously and intraperitoneally but not in intragastrically administered eriodictyol. LC-MS/MS analysis revealed two monoglucuronide metabolites of eriodictyol in liver and intestine microsomes. Recombinant human uridine-5'-diphospho -glucuronosyltransferase (UGT) isoforms and chemical inhibition studies demonstrated that UGT1As (mainly UGT1A1, UGT1A9, UGT1A10) and UGT2B7 were likely the main contributors to eriodictyol glucuronidation. Intragastric administration of eriodictyol, which displayed lower parent and higher metabolite concentrations in the plasma, did not elicit protective effects against APAP hepatotoxicity, when compared to the intraperitoneal injection of eriodictyol. The relative bioavailability of eriodictyol was increased to 216.84% with the coadministration of glycyrrhetinic acid (GA), an inhibitor of UGT1As. Intragastric administration of eriodictyol in combination with GA also induced protective effects against APAP hepatotoxicity. Furthermore, intragastric administration of eriodictyol attenuated APAP hepatotoxicity in heterozygous Ugt1 (Ugt1) mice but not in its wild-type littermates. Thus, UGT1A-mediated metabolic inactivation reduced the protective effect of eriodictyol. Eriodictyol attenuated APAP hepatotoxicity via inhibition of hepatic cytochrome P450 (cyp) 2e1 and cyp3a11 activities; reserve of glutathione (GSH) by improvement of glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glutathione S-transferase (GST) activities; elevation of superoxide dismutase (SOD) activity; and reduction of malondialdehyde (MDA) level. Our findings indicate that parenterally administered eriodictyol may be used to treat APAP-induced hepatotoxicity, and its efficacy can be enhanced by UGT1As down-regulation.
对乙酰氨基酚（APAP）是最常用的口服镇痛药和退烧药之一，但过量服用后可能会发生肝毒性，包括肝功能衰竭。治疗对乙酰氨基酚肝毒性的治疗选择有限。圣草酚，一种具有抗炎和抗氧化特性的饮食类黄酮，用于确定其对小鼠对乙酰氨基酚诱导的肝毒性的保护作用。使用各种给药途径和药代动力学-药效学（PK-PD）分析来确定这些作用。静脉内和腹腔内给予圣草酚可观察到保护作用，但胃内给予圣草酚则没有。LC-MS/MS 分析显示圣草酚在肝脏和肠道微粒体中有两种单葡萄糖醛酸苷代谢物。重组人尿苷-5'-二磷酸-葡萄糖醛酸基转移酶（UGT）同工型和化学抑制研究表明，UGT1A（主要是 UGT1A1、UGT1A9、UGT1A10）和 UGT2B7 可能是圣草酚葡萄糖醛酸化的主要贡献者。与腹腔内注射圣草酚相比，胃内给予显示血浆中母体和代谢物浓度较低的圣草酚，对 APAP 肝毒性没有保护作用。当与甘草酸（GA）合用时，圣草酚的相对生物利用度增加到 216.84%，GA 是 UGT1A 的抑制剂。GA 联合胃内给予圣草酚也诱导了对 APAP 肝毒性的保护作用。此外，胃内给予圣草酚可减轻杂合 Ugt1（Ugt1）小鼠的 APAP 肝毒性，但不能减轻其野生型同窝仔鼠的 APAP 肝毒性。因此，UGT1A 介导的代谢失活降低了圣草酚的保护作用。圣草酚通过抑制肝细胞色素 P450（cyp）2e1 和 cyp3a11 活性；通过提高谷胱甘肽过氧化物酶（GSH-Px）、谷胱甘肽还原酶（GR）和谷胱甘肽 S-转移酶（GST）活性来储备谷胱甘肽（GSH）；通过提高超氧化物歧化酶（SOD）活性；并降低丙二醛（MDA）水平来减轻 APAP 肝毒性。我们的研究结果表明，静脉内给予圣草酚可用于治疗 APAP 诱导的肝毒性，通过下调 UGT1A 可增强其疗效。
