alpha-Tocopherol modulates two major signal transduction pathways centered on
protein kinase C and
phosphatidylinositol 3-kinase. Changes in the activity of these key
kinases are associated with changes in cell proliferation, platelet aggregation, and
NADPH-oxidase activation. Several genes are also regulated by
tocopherols partly because of the effects of
tocopherol on these two
kinases, but also independently of them. These genes can be divided in five groups: Group 1. Genes that are involved in the uptake and degradation of
tocopherols:
alpha-tocopherol transfer protein,
cytochrome P450 (
CYP3A),
gamma-glutamyl-cysteine synthetase heavy subunit, and
glutathione-S-transferase. Group 2. Genes that are implicated with
lipid uptake and
atherosclerosis: CD36, SR-BI, and SR-AI/II. Group 3. Genes that are involved in the modulation of extracellular
proteins:
tropomyosin, collagen-alpha-1, MMP-1,
MMP-19, and
connective tissue growth factor. Group 4. Genes that are connected to adhesion and
inflammation:
E-selectin,
ICAM-1 integrins,
glycoprotein IIb,
IL-2,
IL-4, IL-1b, and
transforming growth factor-beta (
TGF-beta). Group 5. Genes implicated in cell signaling and cell cycle regulation:
PPAR-gamma,
cyclin D1,
cyclin E, Bcl2-L1, p27, CD95 (APO-1/
Fas ligand), and 5a-steroid
reductase type 1. The transcription of p27, Bcl2,
alpha-tocopherol transfer protein,
cytochrome P450 (
CYP3A), gamma-glutamyl-
cysteine sythetase heavy subunit,
tropomyosin,
IL-2, and CTGF appears to be upregulated by one or more
tocopherols. All the other listed genes are downregulated. Gene regulation by
tocopherols has been associated with
protein kinase C because of its deactivation by
alpha-tocopherol and its contribution in the regulation of a number of
transcription factors (NF-kappaB, AP1). A direct participation of the
pregnane X receptor (PXR) /
retinoid X receptor (RXR) has been also shown. The
antioxidant-responsive
element (ARE) and the
TGF-beta-responsive
element (
TGF-beta-RE) appear in some cases to be implicated as well.