Pharmacokinetics and bioavailability of α-, γ- and δ-tocotrienols under different food status

Yap, Siew Ping; Yuen, Kah Hay; Wong, Jeannie Hsiu Ding

doi:10.1211/0022357011775208

Cited by 177 publications

(159 citation statements)

References 11 publications

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“…The lowest IC50 levels in breast cancer cells (McIntyre et al 2000) were obtained by means of days of in vitro exposure to concentrations of HM T3 that are close to, but lower than, the levels of c-and d-T3 found in human and animal plasma after supplementation (Lodge et al 2001;Mustad et al 2002). Furthermore, half life of all T3 investigated in humans (a, c, d) are 4.5-8.7 times shorter than those of a-TOH (Yap et al 2001;Schaffer et al 2005), thus suggesting unfavorable pharmacokinetics of oral administration protocols by sustained liver metabolism.…”

Section: Metabolite Formation and Activitymentioning

confidence: 77%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

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The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (c and d) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated ''highly metabolized'' T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.Keywords Tocotrienols Á Vitamin E Á Breast cancer Á Antioxidants Á Apoptosis Á Cell signaling Á Inflammation Á Metabolism Á Gene expression Á Cell redox T3 structure-function and specificity of actionIn the vitamin E family of molecules, tocotrienols (T3) are often considered of minor importance since these are less abundant than a and c tocopherol (TOH) in the circulation and in solid tissues. This has contributed to hinder our knowledge on the biological functions of this group of vitamers that is now regaining great interest, thanks to a number of recent studies that suggested health-promoting functions related with the cholesterol-lowering, cytoprotective, and anticarcinogenic effects of T3 [reviewed in (Aggarwal et al. (2010)].Structure-function studies demonstrate that many of these functions are more potent when the unsaturated (isoprenyl) side chain of T3 is combined with a hypomethylated (HM) chroman ring. The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson

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Section: Metabolite Formation and Activitymentioning

confidence: 77%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

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“…There were large differences in the antidegranulation effects of α-T3, β-T3, γ-T3, and δ-T3, with the order of the effects being δ-T3 β-T3 γ-T3 α-T3. The strength of the effect may depend on the intracellular concentration 41 and it has been reported that δ-T3 is most easily taken into cells, among the T3 isoforms 42 . Consistent with this finding, examination of the cellular uptake of each T3 isoform in the current study showed that the intracellular level of δ-T3 was especially high Fig.…”

Section: Discussionmentioning

confidence: 99%

Tocotrienol (Unsaturated Vitamin E) Suppresses Degranulation of Mast Cells and Reduces Allergic Dermatitis in Mice

et al. 2013

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“…If this beneficial effect is effective in the ester analogues of T3, the analogues of T3 have a similar advantage as TS as an anticancer agent. The in vivo elimination half life of T3 is quite low compared to T, 14 however, so it is unclear whether the analogues of T3 have a beneficial effect in vivo. Moreover, because the ether bond in T3E is not subjected to enzymatic hydrolysis in vivo, the anticancer property of T3E observed in our study seems to be effective in clinical applications.…”

Section: Discussionmentioning

confidence: 99%

“…12 Tocotrienols and tocopherols, collectively known as vitamin E, are lipid-soluble antioxidants. 13 The in vivo elimination half life of tocotrienols is significantly shorter than that of ␣-tocopherol (T), 14 however, indicating that the tumor-suppressive potential of tocotrienols may be largely weakened in vivo.From recent reports, it seems that the short elimination half life of tocotrienols depends on high metabolic rate and antioxidant property. 15,16 To prolong the elimination half-life and reinforce the anticancer activity of tocotrienols in vivo, it may be a useful procedure to block the antioxidant property of tocotrienols.…”

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Induction of cytotoxicity in human lung adenocarcinoma cells by 6‐O‐carboxypropyl‐α‐tocotrienol, a redox‐silent derivative of α‐tocotrienol

Yano

Satoh

Fukumoto

et al. 2005

Intl Journal of Cancer

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Tocotrienols are one of the most potent anticancer agents of all natural compounds and the anticancer property may be related to the inactivation of Ras family molecules. The anticancer potential of tocotrienols, however, is weakened due to its short elimination half life in vivo. To overcome the disadvantage and reinforce the anticancer activity in tocotrienols, we synthesized a redox-silent analogue of ␣-tocotrienol (T3), 6-O-carboxypropyl-␣-tocotrienol (T3E). We estimated the possibility of T3E as a new anticancer agent against lung adenocarcinoma showing poor prognosis based on the mutation of ras gene. T3E showed cytotoxicity against A549 cells, a human lung adenocarcinoma cell line with a ras gene mutation, in a dose-dependent manner (0 -40 M), whereas T3 and a redox-silent analogue of ␣-tocopherol (T) Key words: ␣-tocotrienol; redox-silent derivative; lung adenocarcinoma; Ras; cytotoxicity; Bcl-xL; cyclin D Lung cancer, particularly non-small cell lung cancer (NSCLC), is one of the most common forms of cancer and is the leading cause of cancer death in the West. 1 NSCLC exhibiting adenocarcinoma histology forms the majority of lung cancers and its ras genes carry mutations. 2 Furthermore, the presence of mutated ras genes in lung adenocarcinoma is linked with shortened patient survival. 3 These reports indicate that signaling pathways activated by mutated Ras protein contribute to the appearance of malignant phenotypes in lung adenocarcinoma. Thus, the inhibition of the mutated Ras function may be a promising procedure to regulate the development of lung cancer.,Mutated Ras proteins remain locked in an active state, and for the activated proteins to transduce the signals into downstream molecules, the proteins must be associated with the inner surface of the plasma membrane. 4 The critical process for the attachment of Ras to the inner surface of the plasma membrane is farnesylation of the C-terminal in Ras protein. 5 Because the inhibition of farnesylation can prevent Ras from maturing into its biologically active form, the inhibition is considered a potential therapeutic procedure for current cancer therapy. 6,7 In general, tumors undergo deregulated cholesterogenesis mainly via the upregulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme of cholesterol synthesis. 8 HMG-CoA reductase plays a key role in controlling cell proliferation by generating prenyl intermediates, particularly farnesyl and geranyl-geranyl moieties, 8 so the upregulation of the enzyme in tumors finally stimulates the cell proliferation via the increase of prenylation in Ras molecules. Thus, agents such as lovastin, which had been exploited previously for lowering cholesterol based on the inhibition of HMG-CoA reductase, may be useful chemotherapeutic agents for treating tumors harboring oncogenic ras mutation. 8 Natural constituents such as sundry mevalonate-derived constituents (isoprenoids) of fruits, vegetables and cereal grains suppress the development of tumors, 9 and the suppressive effect mainly...

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Pharmacokinetics and bioavailability of α-, γ- and δ-tocotrienols under different food status

Cited by 177 publications

References 11 publications

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

Tocotrienol (Unsaturated Vitamin E) Suppresses Degranulation of Mast Cells and Reduces Allergic Dermatitis in Mice

Induction of cytotoxicity in human lung adenocarcinoma cells by 6‐O‐carboxypropyl‐α‐tocotrienol, a redox‐silent derivative of α‐tocotrienol

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