Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1.
Interactions of six naturally occurring flavonoids (acacetin, diosmetin, eriodictyol, hesperetin, homoeriodictyol, and naringenin) with human cytochrome P450 (CYP1) enzymes were studied. The flavones acacetin and diosmetin were potent inhibitors of ethoxyresorufin O-dealkylase (EROD) activity of CYP1A and CYP1B1. Hydroxy and/or methoxy substitutions at the 3' and 4' positions in the flavonoid structures were the major factors involved in conveying selectivity for the different cytochrome P450 enzymes. Eriodictyol, homoeriodictyol and naringenin were very poor inhibitors of human CYP1A EROD activity (IC(50)4 microM). Hesperetin and homoeriodictyol selectively inhibited human CYP1A1 and CYP1B1. Only homoeriodictyol selectively inhibited human CYP1B1 (IC(50) 0.24 microM). Hesperetin was O-demethylated by both human CYP1A1 and 1B1 to eriodictyol, which was then further metabolized by the same enzymes. Hesperetin was not metabolized by human CYP1A2 or CYP3A4.
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U.S. Department of Agriculture, Agricultural Research Service, US Horticultural Research Laboratory, 2001 South Rock Road, Fort Pierce, FL 34945, USA.
Burke
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Mayer
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D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065633:Cytochrome P-450 CYP1B1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000378:metabolism* / Q000494:pharmacology*; D006569:Hesperidin; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology
D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D005419:Flavonoids; D003577:Cytochrome P-450 Enzyme System; D006569:Hesperidin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; C013015:hesperetin