Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products.
Curcumin (diferuloylmethane) is a major yellow pigment and dietary component derived from Curcuma longa. It has potent anti-inflammatory, anticarcinogenic, antioxidant and chemoprotective activities among others. We studied the interactions of curcumin, a mixture of its decomposition products, and four of its individually identified decomposition products (vanillin, vanillic acid, ferulic aldehyde and ferulic acid) on five major human drug-metabolizing cytochrome P450s (CYPs). Curcumin inhibited CYP1A2 (IC(50), 40.0 microM), CYP3A4 (IC(50), 16.3 microM), CYP2D6 (IC(50), 50.3 microM), CYP2C9 (IC(50), 4.3 microM) and CYP2B6 (IC(50), 24.5 microM). Curcumin showed a competitive type of inhibition towards CYP1A2, CYP3A4 and CYP2B6, whereas a non-competitive type of inhibition was observed with respect to CYP2D6 and CYP2C9. The inhibitory activity towards CYP3A4, shown by curcumin may have implications for drug-drug interactions in the intestines, in case of high exposure of the intestines to curcumin upon oral administration. In spite of the significant inhibitory activities shown towards the major CYPs in vitro, it remains to be established, whether curcumin will cause significant drug-drug interactions in the liver, given the reported low systemic exposure of the liver to curcumin. The decomposition products of curcumin showed no significant inhibitory activities towards the CYPs investigated, and therefore, are not likely to cause drug-drug interactions at the level of CYPs.
Appiah-Opong
Regina
R
Division of Molecular Toxicology, Leiden/Amsterdam Center for Drug Research (LACDR), Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Commandeur
Jan N M
JN
van Vugt-Lussenburg
Barbara
B
Vermeulen
Nico P E
NP
D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001547:Benzaldehydes / Q000494:pharmacology; D003373:Coumaric Acids / Q000494:pharmacology; D003474:Curcumin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019388:Cytochrome P-450 CYP1A2; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065702:Cytochrome P-450 CYP2B6; D065729:Cytochrome P-450 CYP2C9; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D014641:Vanillic Acid / Q000494:pharmacology
D001547:Benzaldehydes; D003373:Coumaric Acids; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; C004999:ferulic acid; C100058:vanillin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585599:CYP2B6 protein, human; D019388:Cytochrome P-450 CYP1A2; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D010089:Oxidoreductases, N-Demethylating; D014641:Vanillic Acid; D003474:Curcumin