Document Detail


The discovery of new coding alleles of human CYP26A1 that are potentially defective in the metabolism of all-trans retinoic acid and their assessment in a recombinant cDNA expression system.
MedLine Citation:
PMID:  17460545     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Retinoic acid (RA) is a critical regulator of gene expression during embryonic development and in the maintenance of adult epithelial tissues. This study was undertaken to identify genetic polymorphisms of CYP26A1 which might affect these processes. We sequenced CYP26A1 in racially diverse individuals and assessed the metabolism of retinoic acid by newly identified coding alleles of CYP26A1 in a recombinant system. METHODS: CYP26A1 was sequenced in 24 Caucasians, 24 African-Americans, 24 Asians, and 20 individuals of unknown racial origin. cDNA constructs for wild-type and coding alleles of CYP26A1 were constructed in a pcDNA3.1 expression vector and expressed in Cos-1 cells. A FLAG tag at the C-terminal end of the cDNA was used to quantitate the recombinant CYP26A1 proteins. RESULTS: A total of 13 single nucleotide polymorphisms (SNPs) were identified in CYP26A1. Three SNPs produced coding changes: R173S, F186L, and C358R. These alleles were termed as CYP26A1*2, CYP26A1*3, and CYP26A1*4, respectively, by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee at http://www.cypalleles.ki.se/. Wild type CYP26A1 protein metabolized all-trans-retinoic acid (at-RA) to 4-oxo-RA, 4-OH-RA as well as water-soluble metabolites. CYP26A1.3 (F186L) and CYP26A1.4 (C358R) allelic proteins exhibited significantly lower metabolism (40-80%) of at-RA than wild-type CYP26A1.1 protein. CONCLUSION: This is the first study to identify coding alleles of CYP26A1. Two coding alleles, CYP26A1*3 and CYP26A1*4, are predicted to be defective based on the metabolism of at-RA by the recombinant proteins. These studies suggest the need for future clinical studies of polymorphisms of CYP26A1 in embryonic development.
Authors:
Su-Jun Lee; Lalith Perera; Sherry J Coulter; Harvey W Mohrenweiser; Anton Jetten; Joyce A Goldstein
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  17     ISSN:  1744-6872     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-04-26     Completed Date:  2007-05-18     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  169-80     Citation Subset:  IM    
Affiliation:
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Amino Acid Sequence
Animals
COS Cells
Cercopithecus aethiops
Cytochrome P-450 Enzyme System / genetics*,  metabolism,  physiology*
DNA, Complementary
Gene Expression
Humans
Models, Molecular
Molecular Sequence Data
Polymorphism, Single Nucleotide*
Recombinant Proteins / metabolism
Sequence Homology, Amino Acid
Transfection
Tretinoin / metabolism*
Grant Support
ID/Acronym/Agency:
Y1-ES-8054-05/ES/NIEHS NIH HHS; Z01 ES021024-26/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Complementary; 0/Recombinant Proteins; 302-79-4/Tretinoin; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.14.1/retinoic acid 4-hydroxylase
Comments/Corrections

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


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