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CYP3A Activation and Glutathione Depletion Aggravate Emodin-Induced Liver Injury.
Jiang, Li-Long; Jiang, Yan; Zhao, Dong-Sheng; Fan, Ya-Xi; Yu, Qiong; Li, Ping; Li, Hui-Jun.
Affiliation
  • Jiang LL; State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , China.
  • Jiang Y; Nanjing Forestry University , Nanjing , China.
  • Zhao DS; State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , China.
  • Fan YX; State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , China.
  • Yu Q; State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , China.
  • Li P; State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , China.
  • Li HJ; State Key Laboratory of Natural Medicines , China Pharmaceutical University , Nanjing , China.
Chem Res Toxicol ; 31(10): 1052-1060, 2018 10 15.
Article de En | MEDLINE | ID: mdl-30203651
ABSTRACT
1,3,8-Trihydroxy-6-methylanthraquinone (emodin), a widely existing natural product in herbal medicines, has been reported to be hepatotoxic, but the exact underlying mechanism is still not fully understood. The objective of the present study was to evaluate the role of CYP3A and glutathione (GSH) in emodin-induced liver injury. Primary human hepatocytes were exposed to emodin with and without addition of CYP3A inducer/inhibitor and GSH synthesis inhibitor. It was found that emodin-mediated cytotoxicity increased when CYP3A was activated and GSH was depleted. Hepatotoxicity induced by emodin in rats by activation/inhibition of CYP3A and depletion of GSH was further investigated. Administration of emodin in combination with l-buthionine sulfoximine (BSO) or dexamethasone (DEX) resulted in aggravated liver injury, whereas pretreatment with ketoconazole (KTZ) suppressed the side effects caused by emodin. In addition, plasma exposure of emodin and its glucuronide metabolite were measured by ultraperformance liquid chromatography triple quadrupole mass spectrometry. Emodin and its glucuronide were lower in BSO-, DEX-, and KTZ- co-treated rats compared with those administered with emodin alone. In conclusion, these mentioned results suggested that CYP3A induction and GSH depletion might be involved in hepatotoxicity induced by emodin. This study may help to understand the risk factors and the mechanism of hepatotoxicity of emodin in humans.
Sujet(s)

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Émodine / Cytochrome P-450 CYP3A / Glutathion Type d'étude: Etiology_studies / Risk_factors_studies Limites: Animals / Humans / Male Langue: En Journal: Chem Res Toxicol Sujet du journal: TOXICOLOGIA Année: 2018 Type de document: Article Pays d'affiliation: Chine

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Émodine / Cytochrome P-450 CYP3A / Glutathion Type d'étude: Etiology_studies / Risk_factors_studies Limites: Animals / Humans / Male Langue: En Journal: Chem Res Toxicol Sujet du journal: TOXICOLOGIA Année: 2018 Type de document: Article Pays d'affiliation: Chine