Cortex dictamni-induced liver injury in mice: The role of P450-mediated metabolic activation of furanoids. (15th September 2020)

• Record Type: Journal Article
• Authors: Huang, Linyan; Li, Yi; Pan, Hong; Lu, Yuanfu; Zhou, Xumei; Shi, Fuguo
• Is Part Of: Toxicology letters. Volume 330(2020)
• Page Start: 41
• Page End: 52
• Publication Date: 2020-09-15
• Subjects: CD cortex dictamni -- RM reactive metabolites -- ABT 1-aminobenzotriazole -- DIC dictamnine -- FRA fraxinellone -- OBA obakunone -- LIM limonin -- BSO l-buthionine-S, R-sulfoximine -- NAC N-acetyl-l-cysteine -- GSH glutathione -- DCM dichloromethane -- ALT alanine aminotransferase -- KTZ ketoconazole -- DEX dexamethasone -- H&E hematoxylin and eosin; Cortex dictamni -- Cytochrome P450 -- Furanoids -- Metabolic activation -- Hepatotoxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2020.05.004
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: A single dose of 60 g/kg Cortex Dictamni causes acute liver injury in mice. The liver injury is completely inhibited by P450 non-selective inhibitor. At least 10 furanoids in Cortex Dictamni undergoes P450-mediated bioactivation. The furanoids-derived reactive metabolites are responsible for the hepatotoxicity. Biothiols play a protective effect on the hepatotoxicity. Abstract: Many furan containing compounds have been reported to be toxic resulted from the metabolic activation of the furan ring to reactive metabolite (RM). Cortex Dictamni (CD), a widely used herbal medicine, has been reported to cause severe even fatal hepatotoxicity. The injurious components and mechanism of CD-induced liver injury remain unclear. Our preliminary study showed that dictamnine, one major furanoid in CD, caused mouse liver injury via its reactive epoxide metabolite. Besides dictamnine, the major components of CD are series of bioactivation-alerting furanoids. Thus, we hypothesize that series of furanoids in CD may undergo metabolic activation and play a key role in CD-induced liver injury. Here, a single oral dose of 60 g/kg ethanol extract of CD (ECD) caused severe hepatocellular necrosis in mice at 24 h post-dose. ECD-induced liver injury showed a dose- and time-dependent manner. The hepatotoxic effects could be completely abolished by P450 nonselective inhibitor 1-aminobenzotriazole (ABT) and strongly modulated by other P450 modulators. The furanoids-concentrated fraction of ECD was responsible for the hepatotoxicity. At least ten furanoids with high abundance in ECD, such as obakunone, dictamnine, fraxinellone, limonin, were found to be metabolized to reactive epoxide or cis -enedione. The RM levels were consistent with the liver injury degree. Multiple furanoids, rather than single one, cooperatively contributed to the hepatotoxicity. ECD-induced liver injury could be reproduced by a mixture of pure furanoids. In summary, this study provides toxic component profiles of CD and demonstrates that P450-mediated bioactivation of multiple furanoids is responsible for CD-induced liver injury.