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 |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
- Abcg2 protein, rat
- Diterpenes
- Epoxy Compounds
- 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 Transporter, Subfamily B, Member 1
(antagonists & inhibitors, metabolism)
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- 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
- 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)
|