α‐ and γ‐tocotrienols are metabolized to carboxyethyl‐hydroxychroman derivatives and excreted in human urine

Lodge, John K.; Ridlington, James W.; Leonard, Scott W.; Vaule, Heather; Traber, Maret G.

doi:10.1007/s11745-001-0666-z

Cited by 119 publications

(68 citation statements)

References 21 publications

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“…Indeed, the majority of data obtained assessing the antiproliferative and pro-apoptotic activity of HM T3 in different breast cancer cell lines showed IC50 values between 3 and 30 lM (Table 2) while in non-mammary cells IC50 values are between 20 and 70 lM ( Table 3). 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: 70%

“…The former was defined by the original work of Sen et al (Sen et al 2000) as the prevention activity that a-T3, but not a-TOH, has on glutamate-induced death of T4 hippocampal neuronal cells at nanomolar concentrations that are 4-10 times lower than in plasma. Indeed, a-T3 in human and animal plasma usually reaches maximum 1 lmol/l irrespective of the amount supplemented (Lodge et al 2001;Mustad et al 2002). Therefore, this cytoprotection effect is mediated by physiological T3 concentrations that produced in these neuronal cells c-Src-dependent stimulation of the survival pathway MAPK-ERK, and decreased 12-LOX and eicosanoid pathway activation through a lowered depletion of intracellular glutathione (Sen et al 2004).…”

Section: Metabolite Formation and Activitymentioning

confidence: 99%

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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: 70%

Section: Metabolite Formation and Activitymentioning

confidence: 99%

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

et al. 2011

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“…There have also been some reports about the effects of gtocopherol or g-tocotrienol in humans (Lodge et al, 2001;Galli et al, 2002Galli et al, , 2003. In the study of Galli, a single bolus of 100 mg of deuterium-labeled g-tocopherol acetate (g-TAC) was administered to 21 healthy subjects.…”

Section: Discussionmentioning

confidence: 99%

The effect of γ-tocopherol administration on α-tocopherol levels and metabolism in humans

et al. 2005

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Background: The bioavailability of g-tocopherol and metabolites of vitamin E after g-tocopherol administration is not well understood. We investigated the effect of g-tocopherol administration on the levels and metabolism of a-and g-tocopherol in healthy volunteers. Methods: We measured two metabolites of vitamin E (2,5,7,8-tetramethyl-2-(2 0 -carboxyethyl)-6-hydroxychroman (a-CEHC) and 2,7,8-trimethyl-2-(2 0 -carboxyethyl)-6-hydroxychroman (g-CEHC)) in plasma and urine by high-performance liquid chromatography with electrochemical detection (HPLC-ECD) during administration of g-tocopherol. Two groups of volunteers were enrolled. The g-tocopherol group received two g-tocopherol capsules (each containing 186.4 mg of g-tocopherol and 5 mg of a-tocopherol) for 28 days, while the control group received d-a-tocopherol at 5 mg/day, which was the same dose as that given to the g-tocopherol group. Blood and urine samples were obtained on days 0, 14, 28, 35, 42, and 56 after the initiation of g-tocopherol administration. Results: The plasma g-tocopherol concentration increased markedly during administration of g-tocopherol and the plasma g-CEHC concentration increased along with that of g-tocopherol. The plasma a-tocopherol concentration decreased significantly during g-tocopherol administration. The plasma concentration of a-CEHC decreased significantly and urinary excretion of a-CEHC tended to increase in the g-tocopherol group. Urinary sodium secretion was significantly increased at 1 week after the cessation of g-tocopherol administration, but there was no significant difference of urine volume between the two groups. Conclusion: Metabolism of a-tocopherol is accelerated and the plasma a-tocopherol concentration is decreased during g-tocopherol administration.

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“…T3 were reported to appear in human plasma with half-lives of 4.3, 4.4, and 2.3 h for α-, γ-and δ-T3, respectively [23] , whereas for RRR-α-TOH a half-life of 45 h [110] to 60 h [197] was found. When humans were supplemented with a single dose of 125 mg or 500 mg γ-T3, urinary excretion levels of γ-CEHC rose about 4-to 6-fold with a maximum at 9 h after ingestion and a decline to baseline by the following day [198] . An increase of urinary α-CEHC was only observed after ingestion of a very high dose of α-tocotrienyl acetate (500 mg compared to 125 mg) [198] .…”

Section: Kinetics Of Vitamin E Degradationmentioning

confidence: 99%

Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

178

138

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Bioavailability of vitamin E is influenced by several factors, most are highlighted in this review. While gender, age and genetic constitution influence vitamin E bioavailability but cannot be modified, life-style and intake of vitamin E can be. Numerous factors must be taken into account however, i.e. , when vitamin E is orally administrated, the food matrix may contain competing nutrients. The complex metabolic processes comprise intestinal absorption, vascular transport, hepatic sorting by intracellular binding proteins, such as the significant α-tocopherol-transfer protein, and hepatic metabolism. The coordinated changes involved in the hepatic metabolism of vitamin E provide an effective physiological pathway to protect tissues against the excessive accumulation of, in particular, non-α-tocopherol forms. Metabolism of vitamin E begins with one cycle of CYP4F2/CYP3A4-dependent ω-hydroxylation followed by five cycles of subsequent β-oxidation, and forms the water-soluble end-product carboxyethylhydroxychroman. All known hepatic metabolites can be conjugated and are excreted, depending on the length of their sidechain, either via urine or feces. The physiological handling of vitamin E underlies kinetics which vary between the different vitamin E forms. Here, saturation of the side-chain and also substitution of the chromanol ring system are important. Most of the metabolic reactions and processes that are involved with vitamin E are also shared by other fat soluble vitamins. Influencing interactions with other nutrients such as vitamin K or pharmaceuticals are also covered by this review. All these processes modulate the formation of vitamin E metabolites and their concentrations in tissues and body fluids. Differences in metabolism might be responsible for the discrepancies that have been observed in studies performed in vivo and in vitro using vitamin E as a REVIEW

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α‐ and γ‐tocotrienols are metabolized to carboxyethyl‐hydroxychroman derivatives and excreted in human urine

Cited by 119 publications

References 21 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

The effect of γ-tocopherol administration on α-tocopherol levels and metabolism in humans

Complexity of vitamin E metabolism

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