title: Characterization of metabolites and human P450 isoforms involved in the microsomal metabolism of mesaconitine.
abstract: Mesaconitine (MA), a major Aconitum alkaloid, provides effects against rheumatosis with high toxicity. To supply information for clinical safety, this study aims to investigate the metabolism of MA in male human liver microsomes (MHLMs) and the CYP isoforms involved in its metabolism. Metabolism studies were performed in vitro using MHLMs. Selective chemical inhibitors and recombinant human cytochrome P450 enzymes were used to confirm that the CYP isoforms contributed to MA metabolism. A total of nine metabolites were found and characterized in the MHLM incubations. The metabolic pathways were demethylation, dehydrogenation, hydroxylation, and demethylation-dehydrogenation. Results showed that the inhibitor of CYP3A had a strong inhibitory effect; the inhibitors of CYP2C8, CYP2C9, CYP2C19, and CYP2D6 had modest inhibitory effects, whereas inhibitors of CYP1A2 and CYP2E1 had no obvious inhibitory effects on MA metabolism. Recombinant human cytochrome P450 isoforms CYP3A4 and CYP3A5 contributed greatly to the formation of MA metabolites, and CYP2C8, CYP2C9, and CYP2D6 played a minor role in the formation of MA metabolites. MA could be transformed into at least nine metabolites in MHLMs. MA might be metabolized by CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP2D6 in MHLMs.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ye
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.forename: Yun
authors.initials: Y
authors.lastname: Gong
authors.forename: Chang
authors.initials: C
authors.lastname: Lv
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Zheng
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Jiang
authors.forename: Zhongqiu
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000328:Adult; D000368:Aged; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D013997:Time Factors; D055815:Young Adult
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; C019470:mesaconitine; D003577:Cytochrome P-450 Enzyme System; D000157:Aconitine