CYP-mediated metabolic divergence underpins oxoglaucine selectivity: Detoxification in healthy hepatocytes versus mitochondrial apoptosis in hepatocellular carcinoma.

Oxoglaucine (OXO), an aporphine alkaloid derived from Corydalis yanhusuo, exhibits a broad spectrum of pharmacological activities, including antiviral, antifungal, antiplatelet, and anti-hepatic fibrosis effects, with particularly promising anticancer potential. In this study, we systematically investigated the hepatotoxicity profile and underlying mechanisms of OXO using in vitro models. Dose-response assays revealed that while OXO induced significant cytotoxicity in hepatocytes, primary hepatocytes exhibited markedly reduced sensitivity compared to hepatocellular carcinoma cells at therapeutically relevant concentrations. Mechanistic studies in mouse primary hepatocytes and human primary hepatocytes attributed this selective cytotoxicity to differential cytochrome P450 (CYP) enzyme expression. This finding was functionally validated by the observation that co-treatment with the broad-spectrum CYP inhibitor aminobenzotriazole (ABT) enhanced OXO-induced toxicity in mouse primary hepatocytes and human primary hepatocytes. Regarding its mechanism of toxicity, OXO induced marked cytotoxicity in the HepG2 cell line by triggering mitochondrial-mediated apoptosis, as evidenced by a decreased BCL2/BAX ratio, cytochrome c (CYCS) release, caspase-3 (CASP3) activation, and S-phase cell cycle arrest. Collectively, our findings in HepG2 cells and primary hepatocytes elucidate the role of CYP-mediated metabolism in the selective cytotoxicity of OXO. These findings not only provide crucial mechanistic insights but also support the further development of OXO as a promising candidate for preclinical and clinical evaluation in hepatocellular carcinoma.