title: Advances in molecular modeling of human cytochrome P450 polymorphism.
abstract: Cytochrome P450 (CYP) is a supergene family of metabolizing enzymes involved in the phase I metabolism of drugs and endogenous compounds. CYP oxidation often leads to inactive drug metabolites or to highly toxic or carcinogenic metabolites involved in adverse drug reactions (ADR). During the last decade, the impact of CYP polymorphism in various drug responses and ADR has been demonstrated. Of the drugs involved in ADR, 56% are metabolized by polymorphic phase I metabolizing enzymes, 86% among them being CYP. Here, we review the major CYP polymorphic forms, their impact for drug response and current advances in molecular modeling of CYP polymorphism. We focus on recent studies exploring CYP polymorphism performed by the use of sequence-based and/or protein-structure-based computational approaches. The importance of understanding the molecular mechanisms related to CYP polymorphism and drug response at the atomic level is outlined.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques In Silico, Inserm UMR-S 973, 35 rue Helene Brion, 75013 Paris, France; Inserm, U973, F-75205 Paris, France.
authors.forename: Virginie Y
authors.initials: VY
authors.lastname: Martiny
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D050216:Metabolic Detoxication, Phase I; D008958:Models, Molecular; D011110:Polymorphism, Genetic
chemical_list: D003577:Cytochrome P-450 Enzyme System
keywords: 3D; ADR; DDI; MD; PDB; PM; Protein Data Bank; SNP; UM; adverse drug reactions; cytochrome P450; drug–drug interactions; metabolizing enzymes; miRNA; microRNA; molecular dynamics; molecular modeling; nonsynonymous single nucleotide polymorphism; nsSNP; polymorphism; poor metabolizer; single nucleotide polymorphism; three-dimensional; ultrarapid metabolizer