Assessment of the roles of P-glycoprotein and cytochrome P450 in triptolide-induced liver toxicity in sandwich-cultured rat hepatocyte model.

Abstract

Triptolide (TP), a main bioactive component of Tripterygium wilfordii Hook F., is a promising agent for treatment of autoimmune diseases. However, a high incidence of dose-limiting hepatotoxicity was observed in the clinic. Sandwich-cultured rat hepatocyte model was used in this study to identify the involvement of P-glycoprotein (P-gp) in TP disposition and to evaluate TP-induced hepatotoxicity after modulation of P-gp by the known inhibitors, ritonavir and tariquidar, and known inducers, phenobarbital, quercetin, and H(2)O(2). Our data showed that biliary clearance of TP reduced 73.7% and 84.2% upon treatment of ritonavir (25 µM) and tariquidar (5 µM), respectively. In contrast, increases of 346%, 280%, and 273% in biliary clearance of TP were observed with treatment of phenobarbital (1.0 mM), quercetin (20 µM), and H(2)O(2) (0.5 mM), respectively. The TP-induced hepatotoxicity increased by twofold when CYP activity was blocked by 1-aminobenzotriazole, suggesting that CYP and P-gp may both contribute to the detoxification of TP in the SCRH model. In addition, hepatotoxicity and the expression of apoptosis proteins Bax and Bcl-2 were correlated qualitatively with the TP exposure duration and its intracellular concentration, which, in turn, can be modulated by P-gp inhibitors or inducers. Our results for the first time demonstrated that in addition to CYP-mediated metabolism, P-gp also plays an important role in the disposition of TP and TP-induced hepatotoxicity. Thus, the modulation of canalicular P-gp has a potential to cause drug-drug interaction between TP and the coadministered P-gp inhibitors or inducers in the clinic.

• Authors: Xiao-Mei Zhuang, Guo-Lin Shen, Wei-Bin Xiao, Yan Tan, Chuang Lu, Hua Li
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 41 Issue 12 Pg. 2158-65 (Dec 2013) ISSN: 1521-009X [Electronic] United States
• PMID: 24065861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Abcg2 protein, rat
• Diterpenes
• Epoxy Compounds
• P-Glycoprotein
• Phenanthrenes
• Proto-Oncogene Proteins c-bcl-2
• Quinolines
• bcl-2-Associated X Protein
• triptolide
• Cytochrome P-450 Enzyme System
• Quercetin
• Hydrogen Peroxide
• Cytochrome P-450 CYP3A
• Adenosine Triphosphatases
• tariquidar
• Ritonavir
• Phenobarbital

Topics

• ATP-Binding Cassette Transporters (metabolism)
• Adenosine Triphosphatases (metabolism)
• Animals
• Cytochrome P-450 CYP3A (metabolism)
• Cytochrome P-450 Enzyme System (metabolism)
• Diterpenes (pharmacology)
• Epoxy Compounds (pharmacology)
• Hepatocytes (drug effects, enzymology, metabolism)
• Hydrogen Peroxide (pharmacology)
• Liver (enzymology, metabolism)
• Male
• P-Glycoprotein (antagonists & inhibitors, metabolism)
• Phenanthrenes (pharmacology)
• Phenobarbital (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Quercetin (pharmacology)
• Quinolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Ritonavir (pharmacology)
• bcl-2-Associated X Protein (metabolism)