Inhibition of P-glycoprotein Gene Expression and Function Enhances Triptolide-induced Hepatotoxicity in Mice

• Published in: Scientific reports Vol. 5; no. 1; p. 11747
• Main Authors: Kong, Ling-Lei, zhuang, Xiao-Mei, Yang, Hai-Ying, Yuan, Mei, Xu, Liang, Li, Hua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.07.2015; Nature Publishing Group
• Subjects: 13/2; 13/51; 42/109; 42/89; 631/154/1438; 631/154/570; 64/60; 82/80; Alanine Transaminase - blood; Animals; Apoptosis Regulatory Proteins; Aspartate Aminotransferases - blood; ATP Binding Cassette Transporter, Sub-Family B - genetics; ATP Binding Cassette Transporter, Sub-Family B - metabolism; Autoimmune diseases; Bcl protein; Bcl-2 protein; Cell Line, Tumor; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Data processing; Detoxification; Digoxin; Diterpenes - chemistry; Diterpenes - pharmacokinetics; Diterpenes - toxicity; Drug interaction; Drug interactions; Epoxy Compounds - chemistry; Epoxy Compounds - pharmacokinetics; Epoxy Compounds - toxicity; Gene expression; Gene Knockdown Techniques; Glycoproteins; Hepatocytes; Hepatotoxicity; Humanities and Social Sciences; Immunologic Factors - chemistry; Immunologic Factors - pharmacokinetics; Immunologic Factors - toxicity; Liver; Male; Mice, Inbred BALB C; Molecular Docking Simulation; multidisciplinary; Multidrug resistance; Oxidative Stress; P-Glycoprotein; Phenanthrenes - chemistry; Phenanthrenes - pharmacokinetics; Phenanthrenes - toxicity; Protein Binding; Quinolines - chemistry; Quinolines - pharmacology; RNA, Small Interfering - genetics; Rodents; Science; siRNA; Therapeutic applications; Toxicity; Triptolide
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep11747

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.