title: Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation.
abstract: We investigated the elimination routes for the 200 drugs that are sold most often by prescription count in the United States. The majority (78%) of the hepatically cleared drugs were found to be subject to oxidative metabolism via cytochromes P450 of the families 1, 2 and 3, with major contributions from CYP3A4/5 (37% of drugs) followed by CYP2C9 (17%), CYP2D6 (15%), CYP2C19 (10%), CYP1A2 (9%), CYP2C8 (6%), and CYP2B6 (4%). Clinically well-established polymorphic CYPs (i.e., CYP2C9, CYP2C19, and CYP2D6) were involved in the metabolism of approximately half of those drugs, including (in particular) NSAIDs metabolized mainly by CYP2C9, proton-pump inhibitors metabolized by CYP2C19, and beta blockers and several antipsychotics and antidepressants metabolized by CYP2D6. In this review, we provide an up-to-date summary of the functional polymorphisms and aspects of the functional genomics of the major human drug-metabolizing cytochrome P450s, as well as their clinical significance.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany. uli.zanger@ikp-stuttgart.de
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Miia
authors.initials: M
authors.lastname: Turpeinen
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D015195:Drug Design; D023281:Genomics / Q000379:methods*; D005838:Genotype; D006801:Humans; D009154:Mutation; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D000319:Adrenergic beta-Antagonists; D054328:Proton Pump Inhibitors; D011619:Psychotropic Drugs; D003577:Cytochrome P-450 Enzyme System