title: Gene-gene-environment interactions between drugs, transporters, receptors, and metabolizing enzymes: Statins, SLCO1B1, and CYP3A4 as an example.
abstract: Pharmacogenetic biomarker tests include mostly specific single gene-drug pairs, capable of accounting for a portion of interindividual variability in drug response and toxicity. However, multiple genes are likely to contribute, either acting independently or epistatically, with the CYP2C9-VKORC1-warfarin test panel, an example of a clinically used gene-gene-dug interaction. I discuss here further instances of gene-gene-drug interactions, including a proposed dynamic effect on statin therapy by genetic variants in both a transporter (SLCO1B1) and a metabolizing enzyme (CYP3A4) in liver cells, the main target site where statins block cholesterol synthesis. These examples set a conceptual framework for developing diagnostic panels involving multiple gene-drug combinations.
authors: Program in Pharmacogenomics, Department of Pharmacology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA. wolfgang.sadee@osumc.edu
authors: Wolfgang
authors: W
authors: Sadee
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D059647:Gene-Environment Interaction; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D014859:Warfarin / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D017448:Receptors, Dopamine D2; C503999:SLCO1B1 protein, human; D014859:Warfarin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: drug-metabolizing enzymes; genetic polymorphisms; membrane transport; pharmacogenomics; receptors