title: Inhibitory effects of sanguinarine on human liver cytochrome P450 enzymes.
abstract: Sanguinarine (SAG) has been recognized as an anticancer drug candidate. However, the drug-drug interactions (DDI) potential for SAG via the inhibition against human cytochrome P450 (CYP) enzymes remains unclear. In the present study, the inhibitory effects of SAG on seven major human CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C8, 2C9 and 3A4 were investigated with human liver microsomes (HLM). The results showed that SAG was a potent noncompetitive inhibitor of CYP2C8 activity (Ki=8.9 μM), and competitive inhibitor of CYP1A2, CYP2C9 and CYP3A4 activities (Ki=2.7, 3.8 and 2.0 μM, respectively). Furthermore, SAG exhibited time- and NADPH-dependent inhibition towards CYP1A2 and CYP3A4 with KI/kinact values of 13.3/0.087 and 5.58/0.029 min(-1) μM(-1), respectively. Weak inhibition of SAG against CYP2E1, CYP2D6 and CYP2A6 was also observed. In vitro-in vivo extrapolation (IV-IVE) from HLM data showed that more than 35.9% of CYP1A2, CYP2C9, CYP2C8 and CYP3A4 activities in vivo could be inhibited by SAG, suggesting that harmful DDIs could occur when SAG or its medical preparations are co-administered with drugs primarily cleared by these CYP isoforms. Further in vivo studies are needed to evaluate the clinical significance of the data presented herein.
authors.affiliation: Second Affiliated Hospital of Dalian Medical University, 467 Zhong-shan Road, Dalian, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Qi
authors.forename: Si-Cheng
authors.initials: SC
authors.lastname: Liang
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.forename: Jiang-Wei
authors.initials: JW
authors.lastname: Zhang
authors.forename: Ao-Xue
authors.initials: AX
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.forename: Liang-Liang
authors.initials: LL
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Cai-Xia
authors.initials: CX
authors.lastname: Tu
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053119:Benzophenanthridines / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000378:metabolism
chemical_list: D053119:Benzophenanthridines; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007546:Isoquinolines; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; C005705:sanguinarine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C450259:CYP2C8 protein, human; D019388:Cytochrome P-450 CYP1A2; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human