Inhibition of human cytochrome P450 1A2 by flavones: A molecular modeling study |
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| Authors: | Renke Dai Suoping Zhai Xiaoxiong Wei Matthew R. Pincus Robert E. Vestal Fred K. Friedman |
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| Affiliation: | (1) Laboratory of Molecular Carcinogenesis, National Cancer Institute, 20892 Bethesda, Maryland;(2) Clinical Pharmacology and Gerontology Research Unit, Department of Veterans Affairs Medical Center and Mountain State Medical Research Institute, Boise, Idaho;(3) Department of Pharmaceutical Sciences, College of Pharmacy, Idaho State University, Pocatello, Idaho;(4) Department of Pathology and Laboratory Medicine, Veterans Administration Medical Center, Brooklyn, New York;(5) Department of Pathology, SUNY Health Science Center, Brooklyn, New York;(6) Department of Medicine and Pharmacology, School of Medicine, University of Washington, Seattle, Washington |
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| Abstract: | ![]()
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. |
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| Keywords: | Cytochrome P450 flavones molecular modeling protein folding computational chemistry |
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