Deuterium enrichment of vitamin A at the C20 position slows the formation of detrimental vitamin A dimers in wild-type rodents

J Biol Chem. 2011 Mar 11;286(10):7958-7965. doi: 10.1074/jbc.M110.178640. Epub 2010 Nov 12.

Abstract

Degenerative eye diseases are the most common causes of untreatable blindness. Accumulation of lipofuscin (granular deposits) in the retinal pigment epithelium (RPE) is a hallmark of major degenerative eye diseases such as Stargardt disease, Best disease, and age-related macular degeneration. The intrinsic reactivity of vitamin A leads to its dimerization and to the formation of pigments such as A2E, and is believed to play a key role in the formation of ocular lipofuscin. We sought a clinically pragmatic method to slow vitamin A dimerization as a means to elucidate the pathogenesis of macular degenerations and to develop a therapeutic intervention. We prepared vitamin A enriched with the stable isotope deuterium at carbon twenty (C20-D(3)-vitamin A). Results showed that dimerization of deuterium-enriched vitamin A was considerably slower than that of vitamin A at natural abundance as measured in vitro. Administration of C20-D(3)-vitamin A to wild-type rodents with no obvious genetic defects in vitamin A processing, slowed A2E biosynthesis. This study elucidates the mechanism of A2E biosynthesis and suggests that administration of C20-D(3)-vitamin A may be a viable, long-term approach to retard vitamin A dimerization and by extension, may slow lipofuscin deposition and the progression of common degenerative eye diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Deuterium / chemistry*
  • Dimerization
  • Lipofuscin / biosynthesis*
  • Macular Degeneration / metabolism*
  • Mice
  • Mice, Inbred ICR
  • Pyridinium Compounds
  • Retinoids / biosynthesis*
  • Vitamin A* / chemistry
  • Vitamin A* / pharmacology
  • Vitamins* / chemistry
  • Vitamins* / pharmacology

Substances

  • A2-E (N-retinylidene-N-retinylethanolamine)
  • Lipofuscin
  • Pyridinium Compounds
  • Retinoids
  • Vitamins
  • Vitamin A
  • Deuterium