Evidence for tangeretin O-demethylation by rat and human liver microsomes.
1. Tangeretin, a polymethoxylated flavone, was studied as a substrate for cytochrome P450-catalysed demethylation reactions by rat and human liver microsomes. Evidence has been presented for the production of formaldehyde in the presence of tangeretin and NAD(P)H. Kinetic studies showed a Km value for tangeretin of about 18 microM in both species. 2. The reaction was inhibited by CO, piperonyl butoxide, 7,8-benzoflavone, propyl gallate, aminobenzothiazole and metyrapone. 3. Rats pretreated with classical cytochrome P450 inducers (Aroclor 1254, 3-methylcholanthrene, phenobarbital, dexamethasone and ciprofibrate) or with flavonoids (flavone, flavanone, quercetin and tangeretin) resulted in increased microsomal demethylation of tangeretin after 3-methylcholanthrene and flavone only. Tangeretin did not enhance its own metabolism. 4. Tangeretin interacted with the oxidized form of cytochrome P450 to produce a reverse type I spectrum. 5. Results indicate that tangeretin is metabolized in liver microsomes by an O-demethylation reaction involving cytochrome P450.
Unité de Toxicologie Nutritionnelle, Station de Recherches sur la Qualité des Aliments de l'Homme, Dijon, France.
M C
MC
Canivenc-Lavier
C
C
Brunold
M H
MH
Siess
M
M
Suschetet
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction; D047309:Flavones; D005419:Flavonoids / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008297:Male; D008745:Methylation; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013053:Spectrophotometry / Q000379:methods
D065607:Cytochrome P-450 Enzyme Inhibitors; D047309:Flavones; D005419:Flavonoids; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; C059006:tangeretin