CHEMICO-BIOLOGICAL INTERACTIONS
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2025
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IF 5.4
Tingmin Ye,Chunping Tang,Dandan Yang,Qing Zhang,Yufen Liao,Jie Dai,Hong Tang,Changqiang Ke,Ying Peng,Yang Ye,Weiwei Li,Jiang Zheng
Bavachin (BVC), a flavonoid, is found in Psoraleae fructus (PF) which has been reported to induce various adverse effects, particularly hepatotoxicity, such as increases of serum alanine transaminase and aspartate transaminase in mice given BVC. However, the mechanisms underlying its hepatotoxicity remain unclear. During the incubation of mouse microsomes with BVC in the presence of glutathione (GSH) or N -acetylcysteine (NAC), one oxidative metabolite (M1), one GSH conjugate (M2), and one NAC conjugate (M3) were observed. M1 was successfully synthesized by selective oxidation of BVC. Similar microsomal incubations of synthetic M1 offered M2 and M3. Following oral administration of BVC, the presence of biliary M2 and urinary M3 was observed in mice given BVC. CYP3A identified as the major enzyme was involved in the metabolic activation of BVC. The metabolic activation of BVC involved hydroxylation of BVC and sequential oxidation of the hydroxylation product to the corresponding o -quinone derivative. BVC treatment resulted in significant cytotoxicity in cultured mouse primary hepatocytes, and pretreatment with 1-aminobenzotriazole and ketoconazole decreased the susceptibility of hepatocytes to the cytotoxicity of BVC. Oral administration of PF extract resulted in a quick decline in hepatic GSH, along with the detection of GSH conjugate M2, in mice. BVC, a principal component of PF, was also found to deplete hepatic GSH in mice over a brief period. This evidence suggests that metabolic activation of BVC leads to depletion of GSH in vivo and that BVC contributes to the depletion of hepatic GSH caused by PF extract.
研究领域:
药理学
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毒理学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
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2020
·Vol. 72
·期 12
·1771-1786
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IF 2.571
Li Yang,Xu Chunxia,Xu Jinjin,Qin Zifei,Li Shishi,Hu Liufang,Yao Zhihong,Gonzalez Frank J,Yao Xinsheng
ObjectivesBavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters.MethodsPhase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs.Key findingsFive phase I metabolites (M1–M5) and three glucuronides (G1–G3) were identified. The CLint values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches.ConclusionsCYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.
研究领域:
药理学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
VIRUS RESEARCH
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2018
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IF 2.484
Chen Cheng,Shen Yu-Feng,Hu Yang,Liu Lei,Chen Wei-Chao,Wang Gao-Xue,Zhu Bin
As one of nine piscine viruses recognized by the International Office of Epizootics, spring viraemia of carp virus (SVCV) is an important pathogen bringing high mortality to cyprinids. Up to now, there is no approved therapy on SVCV, making them strong public health threat in aquaculture. In this study, the anti-SVCV activities of 12 plant crude extracts were investigated by using epithelioma papulosum cyprini (EPC) cells. Among these plants, Psoralea corylifolia Linn. showed the highest inhibition on SVCV replication, with an inhibitory percentage of 67.98%. Further studies demonstrated that bavachin (BVN), one of the major constituents of Psoralea corylifolia Linn., was also highly effective to SVCV infection. The half maximal inhibitory concentrations (IC 50 ) of BVN on SVCV glycoprotein and nucleoprotein expression were 0.46 (0.29–0.73) and 0.31 (0.13–0.55) mg/L, respectively. In addition, SVCV-induced apoptosis which may be negative to SVCV replication was inhibited by BVN. The apoptotic cells were decreased 21.42% for BVN compared with SVCV group. These results indicated that the inhibition of BVN on SVCV replication was, in some extent, via blocking SVCV induced apoptosis. Furthermore, cellular morphological damage induced by SVCV was also blocked by BVN treatment. Mechanistically, BVN did not affect SVCV infectivity and cannot be used for prevention of SVCV infection. Time-of-addition and viral binding assays revealed that BVN mainly inhibited the early events of SVCV replication but did not interfere with SVCV adsorption. In conclusion, BVN was considered to develop as a promising agent to treat SVCV infection.
研究领域:
水产养殖学
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病毒学
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药理学
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产品关联
DOI
PubMed
高影响因子
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