title: Inhibition of cytochrome P450 3A by acetoxylated analogues of resveratrol in in vitro and in silico models.
abstract: Many dietary compounds, including resveratrol, are potent inhibitors of CYP3A4. Here we examined the potential to predict inhibition capacity of dietary polyphenolics using an in silico and in vitro approaches and synthetic model compounds. Mono, di, and tri-acetoxy resveratrol were synthesized, a cell line of human intestine origin and microsomes from rat liver served to determine their in vitro inhibition of CYP3A4, and compared to that of resveratrol. Docking simulation served to predict the affinity of the synthetic model compounds to the enzyme. Modelling of the enzyme's binding site revealed three types of interaction: hydrophobic, electrostatic and H-bonding. The simulation revealed that each of the examined acetylations of resveratrol led to the loss of important interactions of all types. Tri-acetoxy resveratrol was the weakest inhibitor in vitro despite being the more lipophilic and having the highest affinity for the binding site. The simulation demonstrated exclusion of all interactions between tri-acetoxy resveratrol and the heme due to distal binding, highlighting the complexity of the CYP3A4 binding site, which may allow simultaneous accommodation of two molecules. Finally, the use of computational modelling may serve as a quick predictive tool to identify potential harmful interactions between dietary compounds and prescribed drugs.
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
authors.forename: Loai
authors.initials: L
authors.lastname: Basheer
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Schultz
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Kerem
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D051381:Rats; D000077185:Resveratrol; D055672:Static Electricity; D013267:Stilbenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D013267:Stilbenes; D013739:Testosterone; D051544:Cytochrome P-450 CYP3A; D000077185:Resveratrol