In vitro and in vivo studies of the metabolic activation of chelidonine.

Chelidonium majus L. is a herbal medicine widely employed in Europe and Western Asia. Chelidonine (CHE) is a major constituent of the herb and has been reported to be an inhibitor of the cytochrome P450 enzymes (CYP). The major objective of the present study was to study the metabolic pathways of CHE in order to identify potential reactive metabolites responsible for the enzyme inhibition. Three oxidative metabolites (M1-M3) were detected in human liver microsomal incubations after exposure to CHE. M1 and M2 were two isomers of catechol derivatives, and M3 was a dicatechol compound. The M1-M3 metabolites were also observed in bile of rats given CHE. A total of five glutathione (GSH) conjugates (M4-M8) were detected in microsomes containing CHE, GSH, and NADPH. Moreover, M4 and M6 originated from M1, M5 and M7 resulted from M2, and M8 was a M3-derived GSH conjugate. Three biliary CHE-derived GSH conjugates (M4, M5 and M8) were found in CHE-treated rats. This indicates that CHE was bioactivated to ortho-quinone derivatives both in vitro and in vivo. Recombinant P450 enzyme incubations demonstrated that the CYPs3A4, 1A2, 2C19 and 2D6 were mainly involved in metabolic activation of CHE. This study generated data that may be useful in understanding possible mechanisms of CHE-induced P450 inhibition.