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CYP450s-Activity Relations of Celastrol to Interact with Triptolide Reveal the Reasons of Hepatotoxicity of Tripterygium wilfordii

by Chunhuan Jin 1,2,†, Zijun Wu 3,†, Lili Wang 3, Yoshikatsu Kanai 2 and Xin He 1,3,*
1
School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Panyu District, Guangzhou 510006, Guangdong, China
2
Department of Bio-system Pharmacology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
3
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jinghai District, Tianjin 301617, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(11), 2162; https://doi.org/10.3390/molecules24112162
Received: 30 April 2019 / Revised: 20 May 2019 / Accepted: 25 May 2019 / Published: 8 June 2019
Celastrol and triptolide, as the two main bio-activity ingredients in Tripterygium wilfordii, have wide anticancer pharmacological potency, as well as anti-inflammatory and immunosuppression effects. However, they have potential hepatotoxicity and underlying mechanisms of them-induced toxicity mediated by hepatic CYP450s have not been well delineated. In the present study, we accessed the toxic effects and possible mechanism of celastrol and triptolide on primary rat hepatocytes. Models of subdued/enhanced activity of CYP450 enzymes in primary rat hepatocytes were also constructed to evaluate the relationship between the two ingredients and CYP450s. LC-MS/MS was used to establish a detection method of the amount of triptolide in rat hepatocytes. As the results, cell viability, biochemical index, and mitochondrial membrane potential indicated that celastrol and triptolide had toxic potencies on hepatocytes. Moreover, the toxic effects were enhanced when the compounds combined with 1-aminobenzotriazole (enzyme inhibitor) while they were mitigated when combined with phenobarbital (an enzyme inducer). Meanwhile, celastrol could affect the amount of triptolide in the cell. We therefore put forward that increase of triptolide in the cell might be one of the main causes of hepatotoxicity caused by Tripterygium wilfordii. View Full-Text
Keywords: celastrol; triptolide; CYP450 enzymes; hepatotoxicity; drug-drug interaction (DDI) celastrol; triptolide; CYP450 enzymes; hepatotoxicity; drug-drug interaction (DDI)
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Jin, C.; Wu, Z.; Wang, L.; Kanai, Y.; He, X. CYP450s-Activity Relations of Celastrol to Interact with Triptolide Reveal the Reasons of Hepatotoxicity of Tripterygium wilfordii. Molecules 2019, 24, 2162.

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