INHIBITION OF HUMAN CYTOCHROME-P450 1A2 BY FLAVONES - A MOLECULAR MODELING STUDY

Cytochrome P450 1A2 metabolizes a number of important drugs, procarcin ogens, and endogenous compounds. Several flavones, a class of phytoche micals consumed in the human diet, have been shown to differentially i nhibit human P450 1A2-mediated methoxyresorufin demethylase. A molecul ar model of this P450 was constructed in order to elucidate the molecu lar basis of the P450-flavone interaction. Flavone and its 3,5,7-trihy droxy and 3,5,7-trimethoxy derivatives were docked into the active sit e to assess their mode of binding. The site is hydrophobic and include s several residues that hydrogen bond with substituents on the flavone nucleus. The binding interactions of these flavones in the modeled ac tive side are consistent with their relative inhibitory potentials, na mely 3,5,7-trihydroxylflavone > flavone > 3,5,7-trimethoxylAavone, tow ard P450 1A2-mediated methoxyresorufin demethylation.