Induction of phase 2 genes by sulforaphane protects retinal pigment epithelial cells against photooxidative damage

Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10446-51. doi: 10.1073/pnas.0403886101. Epub 2004 Jun 30.

Abstract

The retinal pigment epithelial cell (RPE cell) layer protects the photoreceptors of the retina against oxidative stress. The decline of this capacity is believed to be a major factor in the impairment of vision in age-related macular degeneration. Exposure of human adult RPE cells to UV light at predominantly 320-400 nm (UVA light) in the presence of all-trans-retinaldehyde results in photooxidative cytotoxicity. Significant protection of RPE cells was obtained by prior treatment with phase 2 gene inducers, such as the isothiocyanate sulforaphane or a bis-2-hydroxybenzylideneacetone Michael reaction acceptor. The degree of protection was correlated with the potencies of these inducers in elevating cytoprotective glutathione levels and activities of NAD(P)H:quinone oxidoreductase. In embryonic fibroblasts derived from mice in which the genes for the transcription factor Nrf2, the repressor Keap1, or both Nrf2 and Keap1 were disrupted, the magnitude of resistance to photooxidative damage paralleled the basal levels of glutathione and NAD(P)H:quinone oxidoreductase in each cell type. Demonstration of protection of RPE cells against photooxidative damage by induction of phase 2 proteins may shed light on the role of oxidative injury in ocular disease. Moreover, the finding that dietary inducers provide indirect antioxidant protection suggests novel strategies for preventing chronic degenerative diseases, such as age-related macular degeneration.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticarcinogenic Agents / pharmacology*
  • Antioxidants / metabolism
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • Gene Expression / drug effects
  • Glutathione / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Isothiocyanates
  • Kelch-Like ECH-Associated Protein 1
  • Light / adverse effects
  • Lipid Peroxidation / drug effects
  • Macular Degeneration / drug therapy
  • Macular Degeneration / metabolism*
  • Macular Degeneration / prevention & control
  • Mice
  • Mice, Knockout
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2
  • Oxidative Stress / drug effects*
  • Oxygen / metabolism
  • Pigment Epithelium of Eye / cytology
  • Pigment Epithelium of Eye / drug effects*
  • Pigment Epithelium of Eye / physiology
  • Proteins / genetics
  • Retinoids / toxicity
  • Thiocyanates / pharmacology*
  • Trans-Activators / genetics
  • Transcriptional Activation / drug effects

Substances

  • Anticarcinogenic Agents
  • Antioxidants
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Isothiocyanates
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Nfe2l2 protein, mouse
  • Proteins
  • Retinoids
  • Thiocyanates
  • Trans-Activators
  • NAD(P)H Dehydrogenase (Quinone)
  • sulforaphane
  • Glutathione
  • Oxygen