Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells.
HT4 hippocampal neuronal cells were studied to compare the efficacy of tocopherols and tocotrienol to protect against glutamate-induced death. Tocotrienols were more effective than alpha-tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of alpha-tocopherol. Vitamin E molecules have potent antioxidant properties. Results show that at low concentrations, tocotrienols may have protected cells by an antioxidant-independent mechanism. Examination of signal transduction pathways revealed that protein tyrosine phosphorylation processes played a central role in the execution of death. Activation of pp60(c-Src) kinase and phosphorylation of ERK were observed in response to glutamate treatment. Nanomolar amounts of alpha-tocotrienol, but not alpha-tocopherol, blocked glutamate-induced death by suppressing glutamate-induced early activation of c-Src kinase. Overexpression of kinase-active c-Src sensitized cells to glutamate-induced death. Tocotrienol treatment prevented death of Src-overexpressing cells treated with glutamate. alpha-Tocotrienol did not influence activity of recombinant c-Src kinase suggesting that its mechanism of action may include regulation of SH domains. This study provides first evidence describing the molecular basis of tocotrienol action. At a concentration 4-10-fold lower than levels detected in plasma of supplemented humans, tocotrienol regulated unique signal transduction processes that were not sensitive to comparable concentrations of tocopherol.
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Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA. cksen@socrates.berkeley.edu
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D000818:Animals; D016227:Benzoquinones; D016923:Cell Death; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D002839:Chromans / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003676:Deferoxamine / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects; D015151:Immunoblotting; D047029:Lactams, Macrocyclic; D051379:Mice; D009474:Neurons / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D024508:Tocotrienols; D014162:Transfection; D014810:Vitamin E / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*
D016227:Benzoquinones; D002614:Chelating Agents; D002839:Chromans; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D011809:Quinones; D024508:Tocotrienols; D014810:Vitamin E; D019000:Phosphotyrosine; D018698:Glutamic Acid; C013649:plastochromanol 8; C082032:tocotrienol, alpha; D016392:Proto-Oncogene Proteins pp60(c-src); D003676:Deferoxamine; C001277:geldanamycin