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.
Highlights
Tripterygium wilfordii Hook f. (TWHF) has a long history of use in traditional Chinese medicine for the treatment of autoimmune diseases, such as nephritis, lupus erythematosus and rheumatoid arthritis[1]
The results suggested that P-gp mediated biliary efflux was an important detoxification pathway for TP and modulating efflux transporter mediated TP clearance might cause drug-drug interaction (DDI) related safety concerns
The suppressive effect was measured at 48 h after transfection to evaluate the specificity of small interfering RNA (siRNA) targeted to mdr1a
Summary
Tripterygium wilfordii Hook f. (TWHF) has a long history of use in traditional Chinese medicine for the treatment of autoimmune diseases, such as nephritis, lupus erythematosus and rheumatoid arthritis[1]. Pretreatment of animals with CYP3A inhibitors or inducers could significantly alter TP-mediated hepatotoxicity by affecting its metabolic profile[12,16]. These studies concluded that CYP3A mediated hepatic metabolism was a major clearance and detoxification pathway of TP. In addition to the CYP mediated metabolism, recent studies found that biliary excretion was an important clearance route of TP. The results suggested that P-gp mediated biliary efflux was an important detoxification pathway for TP and modulating efflux transporter mediated TP clearance might cause drug-drug interaction (DDI) related safety concerns. Tariquidar, a specific P-gp inhibitor, was tested in parallel with siRNA for comparison and for assessment of the efflux transporter associated DDI
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