A CYP26B1 polymorphism enhances retinoic acid catabolism and may aggravate atherosclerosis

Mol Med. 2012 May 9;18(1):712-8. doi: 10.2119/molmed.2012.00094.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism*
  • Cell Line
  • Cytochrome P-450 Enzyme System / genetics*
  • Cytochrome P-450 Enzyme System / metabolism
  • Female
  • Gene Expression
  • Genotype
  • Humans
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Protein Transport
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retinoic Acid 4-Hydroxylase
  • Transcription, Genetic / drug effects
  • Tretinoin / metabolism*
  • Tretinoin / pharmacology

Substances

  • RNA, Messenger
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • Retinoic Acid 4-Hydroxylase