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J Biol Chem, Vol. 275, Issue 17, 13049-13055, April 28, 2000

Molecular Basis of Vitamin E Action
TOCOTRIENOL POTENTLY INHIBITS GLUTAMATE-INDUCED pp60^c-Src KINASE ACTIVATION AND DEATH OF HT4 NEURONAL CELLS^*

Chandan K. Sen^§, Savita Khanna^¶, Sashwati Roy, and Lester Packer^¶

From the  Lawrence Berkeley National Laboratory and ^¶ Department of Molecular & Cell Biology, University of California, Berkeley, California 94720

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 -tocopherol in preventing glutamate-induced death. Uptake of tocotrienols from the culture medium was more efficient compared with that of -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 -tocotrienol, but not -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. -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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