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. 2019 Jun 8;24(11):2162.
doi: 10.3390/molecules24112162.

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

Chunhuan Jin  1   2 , Zijun Wu  3 , Lili Wang  4 , Yoshikatsu Kanai  5 , Xin He  6   7
Affiliations

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

Chunhuan Jin et al. Molecules. .

Abstract

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.

Keywords: CYP450 enzymes; celastrol; drug-drug interaction (DDI); hepatotoxicity; triptolide.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structure of two ingredients from Tripterygii wilfordii. (A) Celastrol, and (B) triptolide.
Figure 2
Figure 2
The toxicity of celastrol on primary rat hepatocytes. (A) The relative viability after treatment with a series of concentrations of celastrol. (B–D) The effects of celastrol on LDH, AST, and ROS productions in rat primary hepatocyte, respectively. (E) The MMP after administration of different concentrations of celastrol. Compared with the control cells, * p < 0.05, and ** p < 0.01.
Figure 3
Figure 3
Toxicity of triptolide on primary rat hepatocytes. (A) The relative viability after treatment with a variety of concentrations of triptolide. (B–D) The effects of triptolide on LDH, AST, and ROS productions in rat primary hepatocyte, respectively. (E) MMP levels after treatment with different concentrations of triptolide. Compared with the control group, * p < 0.05, ** p < 0.01.
Figure 4
Figure 4
Influence of celastrol on the cell after preincubation with ABT. (A) The relative viability after treatment with a variety of concentrations of celastrol. (B–D) Cellular LDH, AST, and ROS productions after treatment with celastrol, respectively. (E) The MMP after treatment with different concentrations of celastrol. Compared with the control group, * p < 0.05, and ** p < 0.01; compared with the celastrol group, ^ p < 0.05, and ^^ p < 0.01; compared with ABT treated group, # p < 0.05, and ## p < 0.01.
Figure 5
Figure 5
The effect of triptolide on cell after preincubation with ABT. (A) Relative viability after treatment with a variety of concentrations of triptolide. (B–D) Productions of LDH, AST, and ROS in primary rat hepatocytes after exposure to triptolide, respectively. (E) MMP levels of primary rat hepatocytes after treatment with different concentrations of triptolide. Compared with the control group, * p < 0.05, and ** p < 0.01; compared with triptolide group, ^ p < 0.05, and ^^ p < 0.01; compared with ABT treated group, # p < 0.05, and ## p < 0.01.
Figure 6
Figure 6
The influence of celastrol on cells after PB was treated at the concentration of 40 mg/kg for five days. (A) The relative viability after treatment with a variety of concentrations of celastrol. (B–D) LDH, AST, and ROS in cellular supernate accumulation in treatment with primary rat hepatocytes, respectively. (E) The MMP after exposure to different concentrations of celastrol. Compared with the control group, * p < 0.05, and ** p < 0.01; compared with celastrol group, ^ p < 0.05, and ^^ p < 0.01.
Figure 7
Figure 7
The influence of triptolide on cells after PB was treated at 40 mg/kg for five days. (A) Relative viability after treatment with a variety of concentrations of triptolide. (B–D) Cellular LDH, AST, and ROS accumulations in treatment with primary rat hepatocytes, respectively. (E) The MMP after treatment with different concentrations of triptolide. Compared with the control group, * p < 0.05, ** p < 0.01; compared with triptolide group, ^ p < 0.05, ^^ p < 0.01.
Figure 8
Figure 8
The amount of triptolid in rat primary hepatocyte. (A) Accumulation of triptolid in rat primary hepatocyte after treatment with ABT/PB. (B) Amount of triptolid in rat primary hepatocyte after exposure to a series of concentrations of celasreol. Compared with triptolid group, ** p < 0.01.
Figure 9
Figure 9
The relative viability after cells were treated with celastrol and triptolid. Compared with the control group, a combination of the two compounds caused cell viability to significantly decrease in a dose-dependent manner; ** p < 0.01. Compared with triptolid group, # p < 0.05, and ## p < 0.01.
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References

    1. Tao X.L., Cush J.J., Garret M., Lipsky P.E. A phase I study of ethyl acetate extract of the chinese antirheumatic herb tripterygium wilfordii hook f in rheumatoid arthritis. J. Rheumatol. 2001;28:2160–2167. - PubMed
    1. Chen Y.F., Cai H.D. Investigation of liver damage associated with traditional chinese medicines. Adv. Drug Rea. J. 1999;24:27–32.
    1. Gu S.P., Fan Y.W., Wang L.F., Feng G., Liu S.S., Sheng Y., He X. Analysis on release characteristics of sustained release traditional chinese medicine preparation of leigongteng bilayer tablets based on drug simulating system. Chin. J. Exp. Trad. Med. Formulae. 2015;56:549–567.
    1. Lipsky P.E., Tao X.L. A potential new treatment for rheumatoid arthritis: Thunder god vine. Semin Arthritis Rheum. 1997;26:713–723. doi: 10.1016/S0049-0172(97)80040-6. - DOI - PubMed
    1. Bao J., Dai S.M. A chinese herb tripterygium wilfordii hook f. in the treatment of rheumatoid arthritis: Mechanism, efficacy, and safety. Rheumatol. Int. 2011;31:1123–1129. doi: 10.1007/s00296-011-1841-y. - DOI - PubMed

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