Inhibition of human cytochrome P450 1A2 by flavones: a molecular modeling study

• Published in: Journal of Protein Chemistry Vol. 17; no. 7; pp. 643 - 650
• Main Authors: Dai, R, Zhai, S, Wei, X, Pincus, M R, Vestal, R E, Friedman, F K
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.10.1998
• Subjects: Amino Acid Sequence; Animals; Binding; Binding Sites; Cytochrome; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P450; Cytochromes P450; Demethylation; Enzyme Inhibitors - pharmacology; Flavones; Flavonoids - pharmacology; Humans; Hydrogen bonds; Hydrophobicity; Metabolites; Models, Chemical; Models, Molecular; Molecular biology; Molecular modelling; Molecular Sequence Data; Pharmacology; Proteins; Rats; Sequence Alignment; Substrate Specificity
• ISSN: 0277-8033; 1572-3887; 1573-4943
• DOI: 10.1007/BF02780965

Cytochrome P450 1A2 metabolizes a number of important drugs, procarcinogens, and endogenous compounds. Several flavones, a class of phytochemicals consumed in the human diet, have been shown to differentially inhibit human P450 1A2-mediated methoxyresorufin demethylase. A molecular model of this P450 was constructed in order to elucidate the molecular basis of the P450-flavone interaction. Flavone and its 3,5,7-trihydroxy and 3,5,7-trimethoxy derivatives were docked into the active site to assess their mode of binding. The site is hydrophobic and includes several residues that hydrogen bond with substituents on the flavone nucleus. The binding interactions of these flavones in the modeled active side are consistent with their relative inhibitory potentials, namely 3,5,7-trihydroxylflavone > flavone > 3,5,7-trimethoxylflavone, toward P450 1A2-mediated methoxyresorufin demethylation.