Document Detail


A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis.
MedLine Citation:
PMID:  22415012     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
All-trans retinoic acid, controlled by cytochrome P450, family 26 (CYP26) enzymes, potentially has beneficial effects in atherosclerosis treatment. This study investigates CYP26 subfamily B, polypeptide 1 (CYP26B1) in atherosclerosis and the effects of a genetic polymorphism in CYP26B1 on retinoid catabolism. We found that CYP26B1 mRNA was induced by retinoic acid in human atherosclerotic arteries, and CYP26B1 and the macrophage marker CD68 were colocalized in human atherosclerotic lesions. In mice, Cyp26B1 mRNA was higher in atherosclerotic arteries than in normal arteries. Databases were queried for nonsynonymous CYP26B1 single nucleotide polymorphisms (SNPs) and rs2241057 selected for further studies. Constructs of the CYP26B1 variants were created and used for production of purified proteins and transfection of macrophagelike cells. The minor variant catabolized retinoic acid with significantly higher efficiency, indicating that rs2241057 is functional and suggesting reduced retinoid availability in tissues with the minor variant. rs2241057 was investigated in a Stockholm Coronary Atherosclerosis Risk Factor (SCARF) subgroup. The minor allele was associated with slightly larger lesions, as determined by angiography. In summary, this study identifies the first CYP26B1 polymorphism that alters CYP26B1 capacity to metabolize retinoic acid. CYP26B1 was expressed in macrophage-rich areas of human atherosclerotic lesions, induced by retinoic acid and increased in murine atherosclerosis. Taken together, the results indicate that CYP26B1 capacity is genetically regulated and suggest that local CYP26B1 activity may influence atherosclerosis.
Authors:
Olesya Krivospitskaya; Ali Ateia Elmabsout; Eva Sundman; Leif A Söderström; Olga Ovchinnikova; Andreas C Gidlöf; Nikolai Scherbak; Giuseppe Danilo Norata; Ann Samnegård; Hans Törmä; Samy M Abdel-Halim; Jan-Håkan Jansson; Per Eriksson; Allan Sirsjö; Peder S Olofsson
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-09
Journal Detail:
Title:  Molecular medicine (Cambridge, Mass.)     Volume:  18     ISSN:  1528-3658     ISO Abbreviation:  Mol. Med.     Publication Date:  2012  
Date Detail:
Created Date:  2012-07-09     Completed Date:  2012-11-19     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  9501023     Medline TA:  Mol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  712-8     Citation Subset:  IM    
Affiliation:
Department of Clinical Medicine, School of Health and Medical Sciences, Örebro University, Örebro, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Alleles
Animals
Atherosclerosis / genetics*,  metabolism*
Cell Line
Cytochrome P-450 Enzyme System / genetics*,  metabolism
Female
Gene Expression
Genotype
Humans
Macrophages / drug effects,  metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Polymorphism, Single Nucleotide*
Protein Transport
RNA, Messenger / genetics,  metabolism
Transcription, Genetic / drug effects
Tretinoin / metabolism*,  pharmacology
Chemical
Reg. No./Substance:
0/RNA, Messenger; 302-79-4/Tretinoin; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.14.-/cytochrome P-450 CYP26B1
Comments/Corrections

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