Vitamin E for Nonalcoholic Steatohepatitis: Ready for Prime Time?

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A,Diehl AM, Bass NM, et al.

Hepatology. 2010 Aug;52(2):789-92.

Recent results show that alpha-tocopheryl succinate (alpha-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of alpha-TOS with lower number of methyl substitutions on the aromatic ring were less active than alpha-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on alpha-TOS and delta-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. alpha-tocotrienol (alpha-T3 H) failed to induce apoptosis, while gamma-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

The oil palm tree, Elaeis guineesis, is the source of palm oil, otherwise known as the “tropical golden oil”. To date, Malaysia and Indonesia are the leading producers of palm oil. Palm oil is widely used for domestic cooking in Malaysia. Palm oil is a rich source of phytonutrients such astocotrienols, tocopherol, carotene, phytosterols, squalene, coenzyme Q10, polyphenols, and phospholipids. Although the phytonutrients constitute only about 1% of its weight in crude palm oil, these are the main constituents through which palm oil exhibits its nutritional properties. Among the major health promoting properties shown to be associated with the various types of phytonutrients present in palm oil are anti-cancer, cardio-protection and anti-angiogenesis, cholesterol inhibition, brain development and neuro protective properties, antioxidative defence mechanisms, provitamin A activity and anti-diabetes.

Gamma-tocotrienol promotes TRAIL-induced apoptosis through reactive oxygen species/extracellular signal-regulated kinase/p53-mediated upregulation of death receptors

Kannappan R, Ravindran J, Prasad S, Sung B, Yadav VR, Reuter S, Chaturvedi MM, Aggarwal BB.

Mol Cancer Ther. 2010 Aug;9(8):2196-207. Epub 2010 Aug 3.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily, is in clinical trials for cancer therapy, but its anticancer potential is limited by the development of resistance. We investigated the ability of tocotrienol (T3), an unsaturated vitamin E present in palm oil, rice bran, barley, oats, and wheat germ, to sensitize tumor cells to TRAIL. Results from esterase staining, colony formation, caspase activation, and sub-G(1) cell cycle arrest revealed that gamma-T3 can sensitize human colon cancer cells to TRAIL. When examined for the mechanism, we found that gamma-T3 significantly downregulated the expression of antiapoptotic proteins (c-IAP2 and Bcl-xL). We also found that gamma-T3, but not tocopherol, induced the expression of the TRAIL receptors death receptor (DR)-4 and DR5. This induction was not cell type specific, as upregulation was also found in pancreatic, kidney, and leukemic cells. Upregulation of DRs by gamma-T3 required the production of reactive oxygen species (ROS), and sequestering of ROS abolished both upregulation of the receptors and potentiation of TRAIL-induced apoptosis. Induction of DRs by gamma-T3 also required activation of extracellular signal-regulated kinase 1 (ERK1), as silencing of ERK1 by specific siRNA abrogated the upregulation of TRAIL receptors. Further, induction of DRs by gamma-T3 required the expression of p53 and Bax, as no induction of the receptors was found in colon cancer cells with deletion of these genes. Overall, our results show that gamma-T3 sensitizes tumor cells to TRAIL by upregulating DRs through the ROS/ERK/p53 pathway and by downregulating cell survival proteins.

To determine the bioavailability of tocotrienol complex with gamma-cyclodextrin, the effects of tocotrienol/gamma-cyclodextrin complex on tocotrienol concentration in rat plasma and tissues were studied. Rats were administered by oral gavage an emulsion containing tocotrienol, tocotrienol with gamma-cyclodextrin, or tocotrienol/gamma-cyclodextrin complex. At 3 h after administration, the plasma gamma-tocotrienol concentration of the rats administered tocotrienol/gamma-cyclodextrin complex was higher than that of the rats administered tocotrienol and gamma-cyclodextrin. In order to determine the effect of complexation on tocotrienol absorption, rats were injected with Triton WR1339, which prevents the catabolism of triacylglycerol-rich lipoprotein by lipoprotein lipase, and then administered by oral gavage an emulsion containing tocotrienol, tocotrienol with gamma-cyclodextrin, or tocotrienol/gamma-cyclodextrin complex. The plasma gamma-tocotrienol concentration of the Triton-treated rats administered tocotrienol/gamma-cyclodextrin complex was higher than that of the other Triton-treated rats. These results suggest that complexation of tocotrienol with gamma-cyclodextrin elevates plasma and tissue tocotrienol concentrations by enhancing intestinal absorption.

INTRODUCTION: Vitamin E is beneficial in restoring bone histomorphometric parameters in nicotine-treated rats. This study determined the effectiveness of 3 forms of vitamin E in restoring bone metabolism in nicotine-treated rats.

MATERIAL AND METHODS: Thirty-five male Sprague-Dawley rats were divided into 5 groups: (1) control (C), (2) nicotine cessation (NC), (3) α-tocopherol (ATF), (4) tocotrienol-enhanced fraction (TEF) and (5) γ-tocotrienol (GTT). Treatment was carried out for 4 months. The control group was administered normal saline and olive oil throughout the treatment period while treatment for groups 2-5 was performed in 2 phases. In the first phase, the groups received nicotine 7 mg/kg intraperitoneally for 2 months. The following 2 months, group 2 received normal saline and olive oil while groups 3-5 received ATF, TEF or GTT, 60 mg/kg orally. Pre-treatment and post-treatment serum was collected for bone biochemical marker measurement using the ELISA method.

RESULTS: Nicotine increased serum bone-resorbing cytokines (interleukin-1 and interleukin-6) and the bone resorption marker pyridinoline (PYD) while reducing the bone formation marker osteocalcin after 2 months of nicotine treatment. The parameters failed to improve after nicotine was stopped for 2 months. Supplementation with the 3 forms of vitamin E improved the parameters, i.e. reduced the cytokines and pyridinoline as well as increased the osteocalcin. In addition, the TEF and GTT groups had a higher level of osteocalcin than the control group.

CONCLUSIONS: Nicotine impaired bone metabolism and cessation of nicotine treatment did not reverse the effects. Vitamin E, especially the tocotrienols, restored bone metabolism that was impaired due to nicotine.