Cytochrome P450 Enzyme-Mediated Bioactivation as an Underlying Mechanism of Columbin-Induced Hepatotoxicity
| Autor: | Danyan Zhu, Liping Shi, Wen Xiao, Xiaowei Ji, Xiaozhao Deng, Jiaping Pei |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Necrosis Administration Oral Pharmacology Toxicology Lactones Mice chemistry.chemical_compound Cytochrome P-450 Enzyme System In vivo medicine Animals Humans Liver injury chemistry.chemical_classification Mice Inbred ICR Dose-Response Relationship Drug CYP3A4 General Medicine Glutathione medicine.disease In vitro Enzyme Liver chemistry Ketoconazole Diterpenes medicine.symptom medicine.drug |
| Zdroj: | Chemical Research in Toxicology. 33:940-947 |
| ISSN: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.9b00486 |
| Popis: | Columbin, a furanoid compound, is the major bioactive ingredient of Tinospora sagittata (Oliv.) Gagnep, a traditional Chinese medicine that has been reported to cause liver injury in the clinic. The aim of this study was to investigate the hepatotoxicity caused by columbin and its underlying mechanism. Our results indicated that columbin could result in a dose-dependent increase of mice serum alanine aminotransferase and aspartate aminotransferase after oral treatment with columbin, as well as local spotty necrosis in the liver of mice treated with columbin. No hepatotoxicity was observed in mouse treated with the same dose of tetrahydrocolumbin. Pretreatment with ketoconazole preserved the mice from columbin-induced hepatotoxicity. Further studies suggested that bioactivation of the furan ring played an indispensable role in columbin-caused hepatotoxicity. In vitro and in vivo metabolism studies demonstrated that columbin could be metabolized into the cis-butene-1,4-dial intermediate, which readily reacted with glutathione and N-acetyllysine to form stable adducts. Ketoconazole displayed strong inhibitory effect on the generation of M4 and M5 both in vitro and in vivo. Further recombinant human CYP450 screening demonstrated that CYP3A4 was the major enzyme responsible for columbin bioactivation. The present study demonstrated that columbin was hepatotoxic and CYP3A4-mediated bioactivation of the furan ring would serve as an underlying mechanism for columbin-induced hepatotoxicity. |
| Databáze: | OpenAIRE |
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