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

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.
AuthorsXiao-Mei Zhuang, Guo-Lin Shen, Wei-Bin Xiao, Yan Tan, Chuang Lu, Hua Li
JournalDrug 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
PMID24065861 (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
  • 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)

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