The role of α-tocopherol in preventing disease: from epidemiology to molecular events

https://doi.org/10.1016/S0098-2997(03)00028-1Get rights and content

Abstract

The function of vitamin E has been attributed to its capacity to protect the organism against the attack of free radicals by acting as a lipid based radical chain breaking molecule. More recently, alternative non-antioxidant functions of vitamin E have been proposed and in particular that of a “gene regulator”. Effects of vitamin E have been observed at the level of mRNA or protein and could be consequent to regulation of gene transcription, mRNA stability, protein translation, protein stability and post-translational events. Given the high priority functions assigned to vitamin E, it can be speculated that it would be inefficient to consume it as a radical scavenger. Rather, it would be important to protect vitamin E through a network of cellular antioxidant defences, similarly to what occurs with proteins, nucleic acids and lipids.

Introduction

Vitamin E, as studied in laboratory experiments, in animal and human studies, encompasses the tocopherols, the tocotrienols and some of their ester derivatives (as succinate and acetate); for a recent review see Ricciarelli et al. (2001b). The function of vitamin E has been attributed to its capacity to protect the organism against the attack of free radicals (Azzi et al., 2002b; Ingold et al., 1993; Niki, 1987; Ricciarelli et al., 2001a; Smith et al., 1993) by acting as a lipid based radical chain breaking molecule. More recently, alternative non-antioxidant functions of vitamin E have been proposed and, in particular, that of acting as a “gene regulator”. Effects of vitamin E have been observed at the level of mRNA or protein and could be consequent to regulation of gene transcription, mRNA stability, protein translation, protein stability and post-translational events (Azzi et al., 2002b; Niki, 1987; Ricciarelli et al., 2001a, Ricciarelli et al., 2001b).

The mechanism by which vitamin E produces the above referred cellular events might be in principle related to the known radical chain breaking properties of the molecule. This would imply that regulation of certain cellular functions is entrusted to a controlled production and elimination of lipid soluble free radicals. The biological difficulty of controlling the propagation of radical chain reactions makes this mechanism improbable. Furthermore, if the “antiradical function” of α-tocopherol were the way the molecules regulate cell functions, other similar radical chain breaking molecules would also regulate cell functions, but this is however not the case (Chatelain et al., 1993).

On the other side, given the high priority functions assigned to vitamin E (Azzi et al., 2002a, Azzi et al., 2002b), it would be inefficient to consume it as a radical scavenger. Rather, it would be important to protect vitamin E through a network of cellular antioxidant defences, similarly to what occurs with proteins, nucleic acids and lipids.

The proposal that vitamin E has, similarly to vitamin A and vitamin D derivatives, cell regulatory properties unrelated to its radical chain breaking potential, can be supported by a number of experimental facts. In particular, there is no obvious correlation between radical chain breaking potency of tocopherols and tocotrienols and their in vivo effectiveness as cell regulators (Hoppe and Krennrich, 2000; Weiser et al., 1996). On the contrary, other radical chain breaking molecules are in most cases not effective as cell regulators (Boscoboinik et al., 1995). Furthermore, the plasma concentration of the natural vitamin E form, α-tocopherol, is retained by the organism much better than γ-tocopherol, and all other natural or synthetic derivatives (Brigelius-Flohe and Traber, 1999; Sato et al., 1991; Traber et al., 1992; Traber and Kayden, 1989a, Traber and Kayden, 1989b) suggesting a selection of this molecule for special purposes.

In this review, the aspects related to the protective role of vitamin E and its molecular mechanism of action will be presented.

Section snippets

Pathophysiological aspects of vitamin E

The only human disease directly originating from vitamin E insufficiency is ataxia with selective vitamin E deficiency. This disease has a presentation very similar to Friedreich ataxia (Ben Hamida et al., 1993). A similar syndrome, caused by diminished absorption of the lipid soluble vitamin E, is present in fat malabsorption and in a-β-lipoproteinemia (Triantafillidis et al., 1998). Delayed-onset ataxia has been recently shown to occur in mice knock-outs for the α-tocopherol transfer protein

Molecular aspects of α-tocopherol function

The α-TTP having the role of selecting α-tocopherol from other phenolic diet components and regulating α-tocopherol concentration in plasma, has been retained throughout evolution (Sato et al., 1991). Other proteins, tocopherol-associated proteins and tocopherol-binding proteins, may function as tocopherol regulatory proteins (Blatt et al., 2001; review of Porter, 2003). Tocopherol associated proteins have been described as being involved in the regulation of genes and cell signal transduction (

Regulation of protein kinase C

One of the established mechanisms of α-tocopherol cell regulation involves inhibition of PKC (Boscoboinik et al., 1991a, Boscoboinik et al., 1991b). The latter, in its turn is responsible for the α-tocopherol induced diminution of release of reactive oxygen species by inhibition of NADPH oxidase assembly, lipid oxidation, release of cytokines such as interleukin-1ss and tumor necrosis factor-alpha and decreased adhesion of monocytes to human endothelium (Jialal et al., 2001a). α-Tocopherol

Conclusions

The results presented in this article strongly sustain new mechanistic concepts regarding tocopherols and related compounds. Data discussed here support evidence of a gene regulatory function of α-tocopherol and γ-tocopherol. In some cases, changes in protein levels have not been distinguished between gene expression or message or protein stability. Furthermore, no obvious correlation exists between its free radical chain interrupting properties established to take place only within a lipid

Acknowledgments

The studies reported here were made possible thanks to the support of the Swiss Science Foundation, the Swiss Krebsliga and the Swiss Foundation for the Nutrition Research in Switzerland.

References (95)

  • O. Cachia et al.

    Alpha-tocopherol inhibits the respiratory burst in human monocytes. Attenuation of p47(phox) membrane translocation and phosphorylation

    J. Biol. Chem.

    (1998)
  • O. Cachia et al.

    Monocyte superoxide production is inversely related to normal content of alpha-tocopherol in low-density lipoprotein

    Atherosclerosis

    (1998)
  • S.J. Chang et al.

    Alpha-tocopherol downregulates the expression of GPIIb promoter in HEL cells

    Free Radical Biol. Med.

    (2000)
  • E. Chatelain et al.

    Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols

    Biochim. Biophys. Acta

    (1993)
  • A. Fischer et al.

    Effect of selenium and vitamin E deficiency on differential gene expression in rat liver

    Biochem. Biophys. Res. Commun.

    (2001)
  • K. Houglum et al.

    A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C

    Gastroenterology

    (1997)
  • I. Jialal et al.

    The effect of alpha-tocopherol on monocyte proatherogenic activity

    J. Nutr.

    (2001)
  • P. Kempnà et al.

    Cloning of novel human SEC14p-like proteins: ligand binding and functional properties

    Free Radical Biol. Med.

    (2003)
  • I. Kolleck et al.

    HDL is the major source of vitamin E for type II pneumocytes

    Free Radical Biol. Med.

    (1999)
  • J.F. Liu et al.

    Vitamin C supplementation restores the impaired vitamin E status of guinea pigs fed oxidized frying oil

    J. Nutr.

    (1998)
  • R. Marchioli

    Antioxidant vitamins and prevention of cardiovascular disease: laboratory, epidemiological and clinical trial data

    Pharmacol. Res.

    (1999)
  • M. Meydani

    Vitamin E and atherosclerosis: beyond prevention of LDL oxidation

    J. Nutr.

    (2001)
  • N.K. Özer et al.

    Effect of vitamin E and probucol on dietary cholesterol-induced atherosclerosis in rabbits

    Free Radical Biol. Med.

    (1998)
  • L. Packer et al.

    Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling

    J. Nutr.

    (2001)
  • M. Podda et al.

    Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency

    Biochem. Biophys. Res. Commun.

    (1994)
  • T.D. Porter

    Supernatant protein factor and tocopherol-associated protein: an unexpected link between cholesterol synthesis and vitamin E (review)

    J. Nutr. Biochem.

    (2003)
  • S. Pruthi et al.

    Vitamin E supplementation in the prevention of coronary heart disease

    Mayo Clin. Proc.

    (2001)
  • R. Ricciarelli et al.

    Age-dependent increase of collagenase expression can be reduced by alpha-tocopherol via protein kinase C inhibition

    Free Radical Biol. Med.

    (1999)
  • Y. Sato et al.

    Purification and characterization of the alpha-tocopherol transfer protein from rat liver

    FEBS Lett.

    (1991)
  • J. Schwartz et al.

    p53 in the anticancer mechanism of vitamin E

    Eur. J. Cancer B, Oral Oncol.

    (1993)
  • D. Smith et al.

    The role of alpha-tocopherol as a peroxyl radical scavenger in human low density lipoprotein

    Biochem. Pharmacol.

    (1993)
  • N.G. Stephens et al.

    Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

    Lancet

    (1996)
  • D. Teupser et al.

    Alpha-tocopherol down-regulates scavenger receptor activity in macrophages

    Atherosclerosis

    (1999)
  • M.G. Traber et al.

    Preferential incorporation of alpha-tocopherol vs gamma-tocopherol in human lipoproteins

    Am. J. Clin. Nutr.

    (1989)
  • M.G. Traber et al.

    Discrimination between forms of vitamin E by humans with and without genetic abnormalities of lipoprotein metabolism

    J. Lipid Res.

    (1992)
  • H.D. Vlajinac et al.

    Diet and prostate cancer: a case-control study

    Eur. J. Cancer

    (1997)
  • H. Weiser et al.

    Biodiscrimination of the eight alpha-tocopherol stereoisomers results in preferential accumulation of the four 2R forms in tissues and plasma of rats

    J. Nutr.

    (1996)
  • D. Wu et al.

    Vitamin E and macrophage cyclooxygenase regulation in the aged

    J. Nutr.

    (2001)
  • J. Yamauchi et al.

    Tocopherol-associated protein is a ligand-dependent transcriptional activator

    Biochem. Biophys. Res. Commun.

    (2001)
  • S. Zimmer et al.

    A novel human tocopherol-associated protein: cloning, in vitro expression, and characterization

    J. Biol. Chem.

    (2000)
  • S. Zimmer et al.

    A novel human tocopherol-associated protein: cloning, in vitro expression, and characterization

    J. Biol. Chem.

    (2000)
  • S.O. Andersson et al.

    Lifestyle factors and prostate cancer risk: a case-control study in Sweden

    Cancer Epidem. Biomar. Prev.

    (1996)
  • S. Astley et al.

    Vitamin E supplementation and oxidative damage to DNA and plasma LDL in type 1 diabetes

    Diabetes Care

    (1999)
  • A. Azzi et al.

    Molecular basis of alpha-tocopherol control of smooth muscle cell proliferation

    Biofactors

    (1998)
  • A. Azzi et al.

    Regulation of gene and protein expression by vitamin E

    Free Radical Res.

    (2002)
  • R. Ban et al.

    α-Tocopherol transfer protein expression in rat liver exposed to hyperoxia

    Free Radical Res.

    (2002)
  • C. Ben Hamida et al.

    Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping

    Nat. Genet.

    (1993)
  • Cited by (0)

    View full text