Document Detail


Polymorphisms in human CYP2C8 decrease metabolism of the anticancer drug paclitaxel and arachidonic acid.
MedLine Citation:
PMID:  11668219     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cytochrome P450 (CYP) 2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (Taxol). It is also the predominant P450 responsible for the metabolism of arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs) in human liver and kidney. In this study, we describe two new CYP2C8 alleles containing coding changes: CYP2C8*2 has an Ile269Phe substitution in exon 5 and CYP2C8*3 includes both Arg139Lys and Lys399Arg amino acid substitutions in exons 3 and 8. CYP2C8*2 was found only in African-Americans, while CYP2C8*3 occurred primarily in Caucasians. Neither occurred in Asians. The frequency of the CYP2C8*2 allele was 0.18 in African-Americans, and that of CYP2C8*3 was 0.13 in Caucasians. CYP2C8*1 (wild-type), CYP2C8*2 and CYP2C8*3 cDNAs were expressed in Escherichia coli, and the ability of these enzymes to metabolize both paclitaxel and arachidonic acid was assessed. Recombinant CYP2C8*3 was defective in the metabolism of both substrates. The turnover number of CYP2C8*3 for paclitaxel was 15% of CYP2C8*1. CYP2C8*2 had a two-fold higher Km and two-fold lower intrinsic clearance for paclitaxel than CYP2C8*1. CYP2C8*3 was also markedly defective in the metabolism of arachidonic acid to 11,12- and 14,15-EET (turnover numbers 35-40% that of CYP2C8*1). Thus, CYP2C8*3 is defective in the metabolism of two important CYP2C8 substrates: the anticancer drug paclitaxel and the physiologically important compound arachidonic acid. This polymorphism has important clinical and physiological implications in individuals homozygous for this allele.
Authors:
D Dai; D C Zeldin; J A Blaisdell; B Chanas; S J Coulter; B I Ghanayem; J A Goldstein
Related Documents :
8829479 - Characterization of arachidonic acid metabolites through the 12-lipoxygenase pathway in...
9051719 - Leukotriene c4 from vascular endothelium enhances neutrophil adhesiveness.
3120509 - The pharmacology of arachidonic acid-induced rat paw edema.
2108209 - Kinetics of phospholipase a2, arachidonic acid, and eicosanoid appearance in mouse zymo...
21885479 - The emerging roles of fatty acid translocase/cd36 and the aryl hydrocarbon receptor in ...
2112759 - Pathways of arachidonic acid metabolism in human amnion cells at term.
11242729 - Dental erosion in children: a literature review.
12710649 - Perinatal bile acid metabolism: analysis of urinary unsaturated ketonic bile acids in p...
18178349 - Establishing chitosan coated plga nanosphere platform loaded with wide variety of nucle...
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pharmacogenetics     Volume:  11     ISSN:  0960-314X     ISO Abbreviation:  Pharmacogenetics     Publication Date:  2001 Oct 
Date Detail:
Created Date:  2001-10-22     Completed Date:  2001-12-26     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  9211735     Medline TA:  Pharmacogenetics     Country:  England    
Other Details:
Languages:  eng     Pagination:  597-607     Citation Subset:  IM    
Affiliation:
Laboratories of Pharmacology and Chemistry and Pulmonary and Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Alleles
Antineoplastic Agents, Phytogenic / pharmacokinetics*
Arachidonic Acid / pharmacokinetics*
Aryl Hydrocarbon Hydroxylases*
Cell Line
Cytochrome P-450 Enzyme System / genetics*
Genotype
Humans
Metabolic Clearance Rate
Paclitaxel / pharmacokinetics*
Polymorphism, Genetic / genetics*
Recombinant Proteins / genetics,  pharmacokinetics
Sequence Analysis, DNA / methods
Steroid 16-alpha-Hydroxylase*
Steroid Hydroxylases / genetics*
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Recombinant Proteins; 33069-62-4/Paclitaxel; 506-32-1/Arachidonic Acid; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/Steroid Hydroxylases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C8 protein, human; EC 1.14.14.1/Steroid 16-alpha-Hydroxylase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Phenytoin metabolic ratio: a putative marker of CYP2C9 activity in vivo.
Next Document:  Polymorphism of human Alpha class glutathione transferases.