Organic cation transporter 1 and cytochrome P450s play crucial roles in coptisine- and worenine-induced hepatotoxicity.

Coptisine and worenine, isoquinoline alkaloids prevalent in traditional herbal medicines from Papaveraceae (eg, Corydalis Rhizoma) and Ranunculaceae (eg, Coptidis Rhizoma), exhibit significant pharmacologic effects, including cardioprotective and anticancer properties. However, little information is available concerning coptisine- or worenine-induced toxicity, particularly hepatotoxicity, and the underlying mechanisms. Coptisine and worenine contain methylenedioxyphenyl groups, which may be metabolized by cytochrome P450s (P450s) to form reactive metabolites and subsequently induce toxicity. In this study, we demonstrated coptisine- and worenine-induced hepatotoxicity in vitro (in primary mouse and human hepatocytes) and in vivo (in mice). We also found that coptisine and worenine showed significant hepatic accumulation, likely caused by organic cation transporter 1 (OCT1)-mediated uptake, outweighing multidrug and toxin extrusion 1 (MATE1)-mediated efflux, consistent with the higher expression level of OCT1 relative to MATE1. Furthermore, P450s, including CYP1A2, CYP2D6, and CYP3A4, contributed to the formation of reactive quinone-like metabolites (M1 from coptisine and M2, M3, and M4 from worenine), subsequently leading to hepatotoxicity. Additionally, uridine diphosphate glycosyltransferases (UGTs) attenuated coptisine- or worenine-induced hepatocyte toxicity by reducing the formation of reactive metabolites. In conclusion, the present study demonstrated that OCT1 and P450s play crucial roles in coptisine- and worenine-induced hepatotoxicity and that UGTs alleviate the hepatotoxicity. This study provides critical evidence for the safe use of coptisine, worenine, and related traditional Chinese medicines or natural products containing these compounds. SIGNIFICANCE STATEMENT: Coptisine and worenine, bioactive isoquinoline alkaloids from traditional herbs, induce hepatotoxicity via organic cation transporter 1-driven hepatic accumulation and CYP1A2/2D6/3A4-mediated metabolic activation. Our findings underscore the importance of transport- and metabolism-guided safety evaluations of herbal medicines containing these compounds.