α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells

J Nutr Biochem. 2010 Dec;21(12):1222-31. doi: 10.1016/j.jnutbio.2009.10.010. Epub 2010 Feb 12.

Abstract

Vitamin E has long been identified as a major lipid-soluble chain-breaking antioxidant in mammals. α-Tocopherol is a vitamin E component and the major form in the human body. We propose that, besides its direct chain-breaking antioxidant activity, α-tocopherol may exert an indirect antioxidant activity by enhancing the cell's antioxidant system as a Phase II enzyme inducer. We investigated α-tocopherol's inducing effect on Phase II enzymes and its protective effect on acrolein-induced toxicity in a human retinal pigment epithelial (RPE) cell line, ARPE-19. Acrolein, a major component of cigarette smoke and also a product of lipid peroxidation, at 75 μmol/L over 24 h, caused significant loss of ARPE-19 cell viability, increased oxidative damage, decreased antioxidant defense, inactivation of the Keap1/Nrf2 pathway, and mitochondrial dysfunction. ARPE-19 cells have been used as a model of smoking- and age-related macular degeneration. Pretreatment with α-tocopherol activated the Keap1/Nrf2 pathway by increasing Nrf2 expression and inducing its translocation to the nucleus. Consequently, the expression and/or activity of the following Phase II enzymes increased: glutamate cysteine ligase, NAD(P)H:quinone oxidoreductase 1, heme-oxygenase 1, glutathione S-transferase and superoxide dismutase; total antioxidant capacity and glutathione also increased. This antioxidant defense enhancement protected ARPE-19 cells from an acrolein-induced decrease in cell viability, lowered reactive oxygen species and protein oxidation levels, and improved mitochondrial function. These results suggest that α-tocopherol protects ARPE-19 cells from acrolein-induced cellular toxicity, not only as a chain-breaking antioxidant, but also as a Phase II enzyme inducer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / toxicity*
  • Antioxidants / pharmacology*
  • Cell Line
  • Cell Survival
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione Transferase / metabolism
  • Humans
  • Lipid Peroxidation
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • NAD(P)H Dehydrogenase (Quinone)
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress*
  • Reactive Oxygen Species / metabolism
  • Retinal Pigment Epithelium / cytology
  • Retinal Pigment Epithelium / physiopathology*
  • Smoking / adverse effects
  • Superoxide Dismutase / metabolism
  • alpha-Tocopherol / pharmacology*

Substances

  • Antioxidants
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Reactive Oxygen Species
  • Acrolein
  • Superoxide Dismutase
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • Glutathione Transferase
  • Glutamate-Cysteine Ligase
  • alpha-Tocopherol