title: Mechanism-based inhibition of CYP1A1 and CYP3A4 by the furanocoumarin chalepensin.
abstract: The cytochrome P450 (P450, CYP) 2A6 inhibitor chalepensin was found to inhibit human CYP1A1, CYP1A2, CYP2A13, CYP2C9, CYP2D6, CYP2E1, and CYP3A4 to different extents. CYP1A1 and CYP3A4 underwent pronounced mechanism-based inactivation by chalepensin and had the smallest IC50 ratios of inhibition with NADPH-fortified pre-incubation (IC50(+)) to that without pre-incubation (IC50(-)). CYP2E1 had the least susceptibility to mechanism-based inactivation. This inactivation of CYP1A1 and CYP3A4 exhibited time-dependence, led to a loss of spectrophotometrically detected P450, and could not be fully recovered by dialysis. Pre-incubation with chalepensin did not affect NADPH-P450 reductase activity. Cytosol-supported glutathione conjugation protected CYP3A4 but not CYP1A1 against the inactivation by chalepensin. Cytosolic decomposition of chalepensin may contribute partially to the protection. The high epoxidation activities of CYP1A1, CYP2A6, and CYP3A4 were in agreement with their pronounced susceptibilities to mechanism-based inactivation by chalepensin. Considering both the IC50 values and inactivation kinetic parameters, the threshold concentrations of chalepensin for potential drug interactions through inhibition of CYP2A6 and CYP3A4 were estimated to be consistently low. These results demonstrate that chalepensin inhibits multiple P450s and that epoxidation activity is crucial for the potential drug interaction through mechanism-based inhibition.
authors.affiliation: Laboratory of Drug Metabolism, National Research Institute of Chinese Medicine, Taipei, Taiwan, ROC. ueng@nricm.edu.tw
authors.forename: Yune-Fang
authors.initials: YF
authors.lastname: Ueng
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Kazuma
authors.initials: K
authors.lastname: Kiyotani
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Chang
authors.forename: Wei-Shang
authors.initials: WS
authors.lastname: Lo
authors.forename: Ding-Tzai
authors.initials: DT
authors.lastname: Li
authors.forename: Pei-Lun
authors.initials: PL
authors.lastname: Tsai
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D003600:Cytosol / Q000378:metabolism; D011564:Furocoumarins / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism; D051379:Mice; D009249:NADP / Q000378:metabolism
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; C020740:3-(alpha,alpha-dimethylallyl)psoralen; D009249:NADP; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005978:Glutathione