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In vivo protective effects of chlorogenic acid against triptolide-induced hepatotoxicity and its mechanism.

ABSTRACT: CONTEXT:Triptolide (TP) has outstanding biological activities, but it induces toxicities, particular hepatotoxicity, severely limiting its clinical application. Chlorogenic acid (CGA) has prominently medicinal and nutritional values. However, until now, it is not known whether CGA could mitigate TP-induced hepatotoxicity. OBJECTIVE:This study explored the possible protection of CGA against TP-induced hepatotoxicity and its potential mechanisms, for the first time. MATERIAL AND METHODS:KM mice were treated orally with TP at a single dose of 1?mg/kg at 4?h after being treated with CGA (10, 20 and 40?mg/kg) for seven continuous days. Blood samples were collected at 24?h after TP administration for measurement of serum biomarkers, and hepatic tissues for analysis of potential mechanisms. RESULTS:TP treatment-induced acute hepatotoxicity manifested by the significant elevation in serum alanine transaminase (93.9?U/L), aspartate transaminase (185.8?U/L) and hepatic malondialdehyde (0.637??mol/mg protein), and the remarkable reduction in hepatic glutathione (1.425??g/mg protein), glutathione S-transferase, glutathione peroxidase, superoxide dismutase and catalase (91.7, 320.7, 360.6 and 140.7?U/mg protein, respectively). In contrast, pretreatment with CGA for 7?days effectively attenuated acute liver injury and oxidative stress caused by TP with each ED50 of 44.4, 57.1, 46.6, 22.2, 40.9, 58.1, 86.4 and 61.0?mg/kg, respectively. Furthermore, pretreatment with CGA promoted the accumulation of Nrf2 into the nucleus, and up-regulated mRNA expression of Nrf2-target downstream genes. DISCUSSION AND CONCLUSIONS:Combined CGA medication may probably reduce the risk of TP poisoning, and in-depth mechanisms can be developed around the signal molecules of Nrf2.

SUBMITTER: Wang JM

PROVIDER: S-EPMC6300082 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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In vivo protective effects of chlorogenic acid against triptolide-induced hepatotoxicity and its mechanism.

Wang Jun-Ming JM Chen Rong-Xing RX Zhang Lu-Lu LL Ding Ning-Ning NN Liu Chen C Cui Ying Y Cheng Yong-Xian YX

Pharmaceutical biology 20181201 1

<h4>Context</h4>Triptolide (TP) has outstanding biological activities, but it induces toxicities, particular hepatotoxicity, severely limiting its clinical application. Chlorogenic acid (CGA) has prominently medicinal and nutritional values. However, until now, it is not known whether CGA could mitigate TP-induced hepatotoxicity.<h4>Objective</h4>This study explored the possible protection of CGA against TP-induced hepatotoxicity and its potential mechanisms, for the first time.<h4>Material and ...[more]

PMID: 31070533

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Project description:Background and Objective: Indirect hepatotoxicity is a new type of drug-induced hepatotoxicity in which the character of a drug that may induce its occurrence and the underlying mechanism remains elusive. Previously, we proved that Triptolide (TP) induced indirect hepatotoxicity upon LPS stimulation resulting from the deficiency of cytoprotective protein of hepatocyte. However, whether immune cells participated in TP-induced indirect hepatotoxicity and the way immune cells change the liver hypersensitivity to LPS still need to be deeply investigated. In this study, we tried to explore whether and how macrophages are involved in TP-induced indirect hepatotoxicity. Method: Firstly, TP (500 μg/kg) and LPS (0.1 mg/kg) were administrated into female C57BL/6 mice as previously reported. Serum biochemical indicators, morphological changes, hepatic macrophage markers, as well as macrophage M1/M2 markers were detected. Secondly, macrophage scavenger clodronate liposomes were injected to prove whether macrophages participated in TP-induced indirect hepatotoxicity. Also, the ability of macrophages to secrete inflammatory factors and macrophage phagocytosis were detected. Lastly, reverse docking was used to find the target of TP on macrophage and the possible target was verified in vivo and in RAW264.7 cells. Results: TP pretreatment increased the liver hypersensitization to LPS accompanied by the recruitment of macrophages to the liver and promoted the transformation of macrophages to M1 type. Depletion of hepatic macrophages almost completely alleviated the liver injury induced by TP/LPS. TP pretreatment increased the secretion of pro-inflammatory factors and weakened the phagocytic function of macrophages upon LPS exposure. Reverse docking results revealed that MerTK might be the real target of TP. Conclusion: TP disrupts inflammatory cytokines profile and phagocytic function of hepatic macrophages, resulting in the production of massive inflammatory factors and the accumulation of endotoxin in the liver, ultimately leading to the indirect hepatotoxicity of TP. MerTK might be the target of TP on the macrophage, while the binding of TP to MerTK should be investigated in vivo and in vitro.

Project description:Acetaminophen (APAP) is a widely available antipyretic and analgesic; however, overdose of the drug inflicts severe damage to the liver. It is well established that the hepatotoxicity of APAP is initiated by formation of a reactive metabolite, N‑acetyl‑p‑benzoquinone imine (NAPQI), which can be detoxified by conjugation with reduced glutathione (GSH), a typical antioxidant. We recently found that the blood mRNA expression level of glutathione peroxidase 3 (Gpx3), which catalyzes the oxidation of GSH, is associated with the extent of APAP‑induced hepatotoxicity in mice. The present study was carried out to determine the in vivo and in vitro role of GPx3 in APAP‑induced hepatotoxicity. In in vivo experiments, oral administration of APAP to mice induced liver injury. Such liver injury was greater in males than in females, although no gender difference in the plasma concentration of APAP was found. Female mice had a 2‑fold higher expression of Gpx3 mRNA and higher plasma GPx activity than male mice. 17β‑estradiol, a major female hormone, decreased APAP‑induced hepatotoxicity and increased both the expression of blood Gpx3 mRNA and plasma GPx activity, suggesting that the cytoprotective action of this hormone is mediated by the increase in GPx3. To further clarify the role of GPx3 in APAP‑induced hepatotoxicity, we evaluated the effect of a change in cellular GPx3 expression resulting from transfection of either siRNA‑GPx3 or a GPx3 expression vector on NAPQI‑induced cellular injury (as assessed by a tetrazolium assay) in in vitro experiments using heterogeneous cultured human cell lines (Huh‑7 or K562). NAPQI‑induced cell death was reduced by increased GPx3 and was enhanced by decreased GPx3. These results suggest that GPx3 is an important factor for inhibition of APAP‑induced hepatotoxicity both in vivo and in vitro. To our knowledge, this is the first report to show a hepatoprotective role of cellular GPx3 against APAP‑induced liver damage.

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In vivo protective effects of chlorogenic acid against triptolide-induced hepatotoxicity and its mechanism.

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In vivo protective effects of chlorogenic acid against triptolide-induced hepatotoxicity and its mechanism.

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