Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats

Wang, Jiaying; Jiang, Zhenzhou; Ji, Jin-Zi; Wang, Xinzhi; Wang, Tao; Zhang, Yun; Tai, Ting; Chen, I‐Ming; Sun, Lixin; Li, Xia; Zhang, Luyong

doi:10.1016/j.fct.2013.04.039

Cited by 58 publications

(32 citation statements)

References 55 publications

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“…Studies have reported that TP-induced hepatotoxicity can be attributed to lipid peroxidation and hepatic apoptosis [7, 19], while GA possesses anti-inflammation, antioxidation, and hepatoprotection activities [20, 21] and has recently been reported to protect HepG2 cells against TP-induced oxidative stress [22]. However, it is unknown whether GA has an in vivo protective effect against TP-induced hepatotoxicity, which is clearly worth exploring as Licorice is often used in combination with TWHF.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of 18β‐Glycyrrhetinic Acid against Triptolide‐Induced Hepatotoxicity in Rats

Yang

Wang

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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Triptolide (TP) is the major active component of Tripterygium wilfordii Hook F (TWHF) and possesses multiple pharmacological effects. However, hepatotoxicity of TP which is one of the toxic properties slows its progression in clinical application. 18β-Glycyrrhetinic acid (GA) is the main bioactive ingredient of Licorice (Glycyrrhiza glabra L.), a herbal medicine famous for its detoxification. This study aims to investigate whether GA possesses protective effect against TP-induced hepatotoxicity in rats. TP interference markedly elevated serum levels of ALT, AST, and ALP, caused evident liver histopathological changes, and elevated hepatic TNF-α, IL-6, IL-1β, and IFN-γ as well as nuclear translocation of NF-κB. TP also significantly elevated liver MDA and declined hepatic activities of SOD, CAT, and GSH-Px. Assay of TUNEL and apoptosis proteins (Bax, Bcl-2, and active caspase-3) showed that TP induced severe hepatocellular apoptosis. In contrast, low-dose GA (50 mg/kg) significantly reversed TP-induced changes above. However, high-dose GA (100 mg/kg) had no such effect. Overall, these findings indicated that low-dose GA but not high-dose GA exhibited a protective effect against TP-induced hepatotoxicity in rats by anti-inflammation, antioxidation, and antiapoptosis, which suggests that the doses of GA/Licorice should be carefully considered when used together with TWHF or TWHF preparations.

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Section: Introductionmentioning

confidence: 99%

Protective Effect of 18β‐Glycyrrhetinic Acid against Triptolide‐Induced Hepatotoxicity in Rats

Yang

Wang

et al. 2017

Evidence-Based Complementary and Alternative Medicine

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“…1), a diterpene triepoxide, isolated from Tripterygium wilfordii Hook F. has been used for centuries in traditional Chinese medicines to treat autoimmune and inflammatory disorders such as rheumatoid arthritis, immune complex nephritis, systemic lupus erythematosus, and organ or tissue transplantation rejections (Lipsky and Tao, 1997;Panichakul et al, 2006;Lin et al, 2007;Zhuang et al, 2013). However, the clinical application of TP is greatly limited because of its narrow therapeutic window resulting from its high toxicities Wang et al, 2013). Among the adverse events of TP, liver toxicity is believed to be the main cause of death based on the accumulated evidence in the clinic (Chen and Cai, 1999;Wang et al, 2007;Xue et al, 2009;Chai et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Roles of P-glycoprotein and Cytochrome P450 in Triptolide-induced Liver Toxicity in Sandwich-Cultured Rat Hepatocyte Model

et al. 2013

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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 mM) and tariquidar (5 mM), 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 mM), 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.

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“…Xue et al (2011) reported that inactivation of hepatic P450s abolishes the ability to metabolize triptolide in the liver, subsequently resulting in an increase in bioavailability and toxicity of triptolide in vivo. Oral administration of 1000 and 300 mg/kg/bw/day of triptolide for 14 days indicated female rats to be more sensitive to triptolide induced hepatotoxicity than male rats (Wang et al, 2013). During present studies, however, no significant hepatotoxic effect of triptolide treatment was observed in female rats.…”

Section: Discussionmentioning

confidence: 76%

Effect of triptolide on reproduction of female lesser bandicoot rat,Bandicota bengalensis

Dhar

Singla

2014

Drug and Chemical Toxicology

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Triptolide has been reported to cause antifertility in male rats and mice. However, studies on female rats have been limited. Present study was aimed to evaluate the effects of triptolide on reproduction of wild female rodent pest species, Bandicota bengalensis. Feeding of bait containing 0.1, 0.15 and 0.2% triptolide for a period of 15 days in bi-choice resulted in per day ingestion of 17.37, 23.54 and 27.49 mg/kg body weight of triptolide, respectively. Examination of vaginal smear of all the rats revealed a significant (p ≤ 0.05) increase in duration of estrous cycle due to increase in durations of metestrous and diestrous stages in rats of treated groups. Autopsy of rats after 15 and 30 days of treatment withdrawal revealed significant (p ≤ 0.05) reduction in weights of uterus and ovaries, non-significant reduction in weights of liver and levels of estradiol and progesterone and significant (p ≤ 0.05) reduction in levels of urea and BUN and increase in levels of plasma proteins, ALT, AST, ALP, ACP and LDH in rats of treated groups compared to untreated group. There was no significant (p ≤ 0.05) effect of treatment on body weight. Triptolide treatment affected the histomorphology of uterus by causing a decrease in lumen and columnar cell height and number of uterine glands and ovary by increasing the number of atretic follicles and decreasing the number of developing follicles. The present study suggests triptolide to be a strong candidate affecting reproduction of female B. bengalensis.

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Gene expression profiling and pathway analysis of hepatotoxicity induced by triptolide in Wistar rats

Cited by 58 publications

References 55 publications

Protective Effect of 18β‐Glycyrrhetinic Acid against Triptolide‐Induced Hepatotoxicity in Rats

Protective Effect of 18β‐Glycyrrhetinic Acid against Triptolide‐Induced Hepatotoxicity in Rats

Assessment of the Roles of P-glycoprotein and Cytochrome P450 in Triptolide-induced Liver Toxicity in Sandwich-Cultured Rat Hepatocyte Model

Effect of triptolide on reproduction of female lesser bandicoot rat,Bandicota bengalensis

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