title: Mass spectrometric investigation of chelerythrine and dihydrochelerythrine biotransformation patterns in human hepatocytes.
abstract: The quaternary benzo[c]phenanthridine alkaloids (QBAs) are an important subgroup of plant secondary metabolites. Their main representatives, sanguinarine (SG) and chelerythrine (CHE), have pleiotropic biological effects and a wide spectrum of medicinal applications. The biotransformation of SG and CHE has only been partially studied while subsequent oxidative transformation of their dihydro derivates, the main metabolites, is practically unknown. The aim of this study was to characterize the biotransformation of CHE and dihydrochelerythrine (DHCHE) in detail, with respect to their more extensive biotransformation than SG. Phase I as well as phase II biotransformation of both compounds was examined in human hepatocyte suspensions. Liquid chromatography with electrospray-quadrupole time-of-flight mass spectrometry (LC-ESI-QqTOF MS) was used for analysis of the metabolites. Using the LC-ESI-QqTOF MS method, we analyzed and then suggested the putative structures of 11 phase I and 5 phase II metabolites of CHE, and 11 phase I and 6 phase II metabolites of DHCHE. For the most abundant metabolites of CHE, DHCHE and O-demethylated DHCHE, their cytotoxicity on primary cultures of human hepatocytes was analyzed. Both metabolites were nontoxic up to 50μM concentration and this indicates decreasing toxic effects for CHE biotransformation products, i.e. DHCHE and O-demethylated DHCHE.
authors.affiliation: Department of Medical Chemistry and Biochemistry, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 3, 775 15 Olomouc, Czech Republic. Electronic address: jan.vacek@upol.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Vacek
authors.forename: Barbora
authors.initials: B
authors.lastname: Papoušková
authors.forename: Pavel
authors.initials: P
authors.lastname: Kosina
authors.forename: Adéla
authors.initials: A
authors.lastname: Galandáková
authors.forename: Jitka
authors.initials: J
authors.lastname: Ulrichová
mesh_terms: D053119:Benzophenanthridines / Q000493:pharmacokinetics*; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D053119:Benzophenanthridines; C524982:dihydrochelerythrine; C016299:chelerythrine
keywords: Benzo[c]phenanthridines; Chelerythrine; Dihydrochelerythrine; Human hepatocytes; Metabolic transformation