title: Inhibition of P-glycoprotein Gene Expression and Function Enhances Triptolide-induced Hepatotoxicity in Mice.
abstract: Triptolide (TP) is the major active principle of Tripterygium wilfordii Hook f. and very effective in treatment of autoimmune diseases. However, TP induced hepatotoxicity limited its clinical applications. Our previous study found that TP was a substrate of P-glycoprotein and its hepatobiliary clearance was markedly affected by P-gp modulation in sandwich-cultured rat hepatocytes. In this study, small interfering RNA (siRNA) and specific inhibitor tariquidar were used to investigate the impact of P-gp down regulation on TP-induced hepatotoxicity. The results showed that when the function of P-gp was inhibited by mdr1a-1 siRNA or tariquidar, the systemic and hepatic exposures of TP were significantly increased. The aggravated hepatotoxicity was evidenced with the remarkably lifted levels of serum biomarkers (ALT and AST) and pathological changes in liver. The other toxicological indicators (MDA, SOD and Bcl-2/Bax) were also significantly changed by P-gp inhibition. The data analysis showed that the increase of TP exposure in mice was quantitatively correlated to the enhanced hepatotoxicity, and the hepatic exposure was more relevant to the toxicity. P-gp mediated clearance played a significant role in TP detoxification. The risk of herb-drug interaction likely occurs when TP is concomitant with P-gp inhibitors or substrates in clinic.
authors.affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Ling-Lei
authors.initials: LL
authors.lastname: Kong
authors.affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Zhuang
authors.affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Hai-Ying
authors.initials: HY
authors.lastname: Yang
authors.affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yuan
authors.affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics* / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001219:Aspartate Aminotransferases / Q000097:blood; D045744:Cell Line, Tumor; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D004077:Digoxin; D004224:Diterpenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D004852:Epoxy Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D055785:Gene Knockdown Techniques; D007155:Immunologic Factors / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D008297:Male; D008807:Mice, Inbred BALB C; D062105:Molecular Docking Simulation; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D011485:Protein Binding; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D004852:Epoxy Compounds; D007155:Immunologic Factors; D010616:Phenanthrenes; D011804:Quinolines; D034741:RNA, Small Interfering; C001899:triptolide; D004077:Digoxin; C095122:multidrug resistance protein 3; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C402343:tariquidar