8-methoxypsoralen protects against acetaminophen-induced liver injury by antagonising Cyp2e1 in mice.

Autor: Liu S; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Cheng R; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., He H; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Ding K; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Zhang R; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Chai Y; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Yu Q; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: yuqinwei7213@cpu.edu.cn., Huang X; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China., Zhang L; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou, 510006, China., Jiang Z; New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: beaglejiang@cpu.edu.cn.
Jazyk: angličtina
Zdroj: Archives of biochemistry and biophysics [Arch Biochem Biophys] 2023 Jun; Vol. 741, pp. 109617. Date of Electronic Publication: 2023 Apr 29.
DOI: 10.1016/j.abb.2023.109617
Abstrakt: This study aimed to investigate the effect and mechanism of 8-methoxypsoralen (8-MOP) on acetaminophen (APAP)-induced hepatotoxicity in mice. The study found that 1 h after intraperitoneal injection of 300 mg/kg APAP, treatment with 40 mg/kg, 80 mg/kg and 120 mg/kg 8-MOP could reduce serum transaminase level and histopathological liver necrosis area. Elevated mRNA expression of liver inflammatory mediators caused by excessive APAP was also reversed. 8-MOP significantly reduced APAP-induced hepatotoxicity dose-dependently, and the highest therapeutic dose of 8-MOP (120 mg/kg) had no harmful effects on the liver. Cocktail probe assay revealed that 8-MOP can inhibit Cyp2e1 enzymatic activities of mice, thereby reducing the production of acetaminophen-cysteine (APAP-CYS), a toxic metabolite of APAP. 8-MOP had no significant effect on the protein and gene expression of Cyp2e1. The three-dimensional structures of mouse Cyp2e1 were constructed by homologous modeling. Molecular docking showed that 8-MOP had a good binding effect on the enzyme activity site of Cyp2e1. In summary, 8-MOP dose-dependently attenuated APAP-induced hepatotoxicity by binding to Cyp2e1 and occupying the active center of the enzyme, thus competitively inhibiting the oxidative metabolism of APAP, and reducing the generation of toxic product APAP-CYS.
Competing Interests: Declaration of competing interest There is no conflict of interest between the authors and anyone or any institution associated with this study.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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