| Impact of genetic polymorphisms in CYP2C8 and rosiglitazone intake on the urinary excretion of dihydroxyeicosatrienoic acids. | |
| | |
MedLine Citation:
|
PMID: 18303964 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The cytochrome P450 enzymes CYP2C8, CYP2C9 and CYP2J2 generate 8,9-, 11,12-, and 14,15-epoxyeicosatrienic acid (EET) from arachidonic acid, and these EETs are then hydrolyzed to dihydroxyeicosatrienoic acids (DHET) before excretion into the urine. It is unknown how genetic polymorphisms affect formation of these diuretic, vasodilatory and anti-inflammatory eicosanoids, and whether the CYP2C8 substrate rosiglitazone inhibits their formation. METHODS: A panel of 14, 13 and four carriers of the CYP2C8 genotypes *1/*1, *1/*3 and *3/*3, respectively was preselected for this study. Daily morning oral doses of 8 mg rosiglitazone were administered for 15 days. Urine was collected prior to rosiglitazone, and for 24 h after the first and last administration of rosiglitazone. Urinary EETs and DHETs were analyzed by tandem mass spectrometry. RESULTS: Carriers of the high-activity CYP2C8*3 allele had higher excretion of all three DHETs (p < 0.01 for 11,12-DHET, p < 0.05 for 14,15-DHET), whereas carriers of the low-activity CYP2C8 haplotype C (genotypes GCGA at positions rs2275622, rs7909236, rs1113129 and rs11572080) had lower DHET excretion in urine before and during rosiglitazone. Rosiglitazone intake leads to a decrease in DHET excretion by approximately 10% (p < 0.02). Urinary excretion of unhydrolyzed EETs was below the limit of quantification of 50 pg/ml in all samples. CONCLUSION: The data consistently indicate that genetic variation in CYP2C8 moderately modulates-EET formation as reflected in urinary DHET excretion. This might impact cardiovascular functions, and may be one mechanism explaining the influence of CYP polymorphisms on myocardial infarction and hypertension. |
| | |
Authors:
|
Julia Kirchheiner; Ingolf Meineke; Uwe Fuhr; Cristina Rodríguez-Antona; Elena Lebedeva; Jürgen Brockmöller |
Related Documents
:
|
7251734 - Longitudinal urinary excretion of some "trace" acids in a human male. 131054 - Alaskan malamute chondrodysplasia. ii. urinary excretion of hydroxyproline, uronic acid... 2232494 - Removal of an inorganic acid load in subjects with ketoacidosis of chronic fasting. 10844694 - Identification of a major facilitator protein from escherichia coli involved in efflux ... 12531704 - Photoelectrocatalytic degradation of 4-chlorophenol and oxalic acid on titanium dioxide... 11312944 - Mimicry of peptide backbone geometry and heteroatomic side-chain functionality: synthes... |
Publication Detail:
|
Type: Journal Article |
Journal Detail:
|
Title: Pharmacogenomics Volume: 9 ISSN: 1744-8042 ISO Abbreviation: Pharmacogenomics Publication Date: 2008 Mar |
Date Detail:
|
Created Date: 2008-02-28 Completed Date: 2008-04-25 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 100897350 Medline TA: Pharmacogenomics Country: England |
Other Details:
|
Languages: eng Pagination: 277-88 Citation Subset: IM |
Affiliation:
|
Institute of Pharmacology of Natural Products and Clinical Pharmacology, University Ulm, Helmholtzstr. 20, 89081 Ulm, Germany. julia.kirchheiner@uni-ulm.de |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Aryl Hydrocarbon Hydroxylases
/
genetics* Female Genotype Heterozygote Detection Humans Hydroxyeicosatetraenoic Acids / urine* Hypoglycemic Agents / pharmacology Male Polymerase Chain Reaction Polymorphism, Genetic* Thiazolidinediones / pharmacology* |
| Chemical | |
Reg. No./Substance:
|
0/Hydroxyeicosatetraenoic Acids; 0/Hypoglycemic Agents; 0/Thiazolidinediones; 122320-73-4/rosiglitazone; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/CYP2C8 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Distribution of ABCB1 polymorphisms among Brazilians: impact of population admixture.
Next Document: Effect of a ciliary neurotrophic factor polymorphism on schizophrenia symptom improvement in an ilop...