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

Kong LL, Zhuang XM, Yang HY, Yuan M, Xu L, Li H - Sci Rep (2015)

Bottom Line: 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.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.P-gp mediated clearance played a significant role in TP detoxification.

View Article: PubMed Central - PubMed

Affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

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.

No MeSH data available.


Related in: MedlinePlus

Chemical structure of triptolide.
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f1: Chemical structure of triptolide.

Mentions: TP (Fig. 1) was obtained from National Institutes for Food and Drug Control (Beijing, China) with the purity >99%. Tariquidar was purchased from Sigma (St. Louis, MO, USA). The siRNA was chemically synthesized by Ribobio Co., Ltd (Guangzhou, China). The rabbit anti-P-gp was obtained from Abcam (Cambridge, UK). The mouse anti-Bcl-2 and anti-Bax were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Horseradish peroxidase (HRP)-conjugated secondary antibodies were from Pierce Biotechnology (Thermo Fisher Scientific, Rockford, IL, USA). Acetonitrile and Methanol were of HPLC grade (J&K Chemical LTD) and other reagents were all of analytical grade.


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

Kong LL, Zhuang XM, Yang HY, Yuan M, Xu L, Li H - Sci Rep (2015)

Chemical structure of triptolide.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4488747&req=5

f1: Chemical structure of triptolide.
Mentions: TP (Fig. 1) was obtained from National Institutes for Food and Drug Control (Beijing, China) with the purity >99%. Tariquidar was purchased from Sigma (St. Louis, MO, USA). The siRNA was chemically synthesized by Ribobio Co., Ltd (Guangzhou, China). The rabbit anti-P-gp was obtained from Abcam (Cambridge, UK). The mouse anti-Bcl-2 and anti-Bax were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). Horseradish peroxidase (HRP)-conjugated secondary antibodies were from Pierce Biotechnology (Thermo Fisher Scientific, Rockford, IL, USA). Acetonitrile and Methanol were of HPLC grade (J&K Chemical LTD) and other reagents were all of analytical grade.

Bottom Line: 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.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.P-gp mediated clearance played a significant role in TP detoxification.

View Article: PubMed Central - PubMed

Affiliation: 1] State Key Laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China [2] Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

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.

No MeSH data available.


Related in: MedlinePlus