Elucidation of Cortex Dictamni hepatotoxicity mechanisms through toxic component identification and integrated multi-omics analysis

Abstract

Ethnopharmacological relevance: Cortex Dictamni (CD), the root bark of Dictamnus dasycarpus, is a traditional East Asian medicine historically used to treat inflammatory skin conditions (e.g., eczema, urticaria), rheumatic disorders, and jaundice, primarily valued for its anti-inflammatory and immunomodulatory properties. Despite its therapeutic history, clinical reports indicate significant hepatotoxicity risks. The precise toxic components and mechanisms underlying this liver injury remain poorly defined.

Aim of the study: This study aimed to identify hepatotoxic components in CD and elucidate their mechanisms by evaluating solvent-extracted fractions derived from CD ethanol extract (ECD).

Materials and methods: Hepatotoxicity was assessed through in vitro cytotoxicity assays and in vivo murine models. Chemical profiling identified enriched constituents in toxic fractions, with systemic exposure confirmed via plasma pharmacochemistry. Subchronic toxicity studies evaluated dose-dependent liver injury using serum ALT/AST, histopathology, and metabolic analyses. Integrated transcriptomics and metabolomics delineated disrupted biological pathways.

Results: The petroleum ether (PE) fraction demonstrated the highest hepatotoxicity. Chemical profiling revealed enrichment of furan-containing compounds (particularly furanoterpenoids) in PE, which entered systemic circulation. PE exposure induced dose-dependent liver injury in mice, evidenced by elevated ALT/AST, histopathological damage, and disruption of retinol, histidine, glutathione, and drug metabolism pathways. Multi-omics analysis linked toxicity to oxidative stress and mitochondrial dysfunction.

Conclusions: Furanoterpenoids were identified as primary hepatotoxicants in CD. Their synergistic disruption of metabolic and redox pathways underlies CD-induced liver injury. These findings provide critical insights for the safer clinical application of CD-containing formulations.

Keywords: Cortex Dictamni; Furanoterpenoids; Hepatotoxicity; Multi-omics.