title: Identification of cytochrome P450 (CYP) isoforms involved in the metabolism of corynoline, and assessment of its herb-drug interactions.
abstract: Corynoline, an isoquinoline alkaloid isolated from the genus Corydalis, has been demonstrated to show multiple pharmacological effects including inhibition of acetylcholinesterase, inhibition of cell adhesion, fungitoxic and cytotoxic activity. The present study focused on its metabolism and metabolism-based herb-drug interactions. After corynoline was incubated with human liver microsomes (HLMs) in the presence of NADPH, two metabolites (M-1 and M-2) were formed. Chemical inhibition experiments and assays with recombinant CYP isoforms showed that CYP2C9 was mainly involved in the formation of M-1 and CYP3A4 mainly catalysed the production of M-2. Among seven major CYP isoforms tested, corynoline showed strong inhibitory effects on the activities of CYP3A4 and CYP2C9, with an IC(50) of 3.3 ± 0.9 µm and 31.5 ± 0.5 µm, respectively. Kinetic analysis showed that inhibition of CYP3A4 by corynoline was best fit to a noncompetitive manner with K(i) of 3.2 µm, while inhibition of CYP2C9 by corynoline was best fit to a competitive manner with K(i) of 6.3 µm. Additionally, corynoline exhibited time-dependent inhibition (TDI) toward CYP3A4. The inactivation kinetic parameters (K(I) and k(inact) ) were calculated to be 6.8 µm and 0.07 min(-1) , respectively. These data are of significance for the application of corynoline and corynoline-containing herbs.
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhang
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.forename: Si-Cheng
authors.initials: SC
authors.lastname: Liang
authors.forename: Dong-Xue
authors.initials: DX
authors.lastname: Sun
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Zhu
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001600:Berberine Alkaloids / Q000378:metabolism / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D041743:Herb-Drug Interactions; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D013997:Time Factors
chemical_list: D001600:Berberine Alkaloids; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C487644:corynoline; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human