Discovery, Characterization, and Significance of the Cytochrome P450 ω‐Hydroxylase Pathway of Vitamin E Catabolism

Parker, Robert S.; Sontag, Timothy J.; Swanson, Joy E.; McCormick, Charles C.

doi:10.1196/annals.1331.002

Cited by 51 publications

(41 citation statements)

References 13 publications

(14 reference statements)

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“…1). On the other hand, the pathway of the ␣-and ␥-tocopherol metabolism to ␣-and ␥-CEHC involveshydroxylation of phytyl chains and the following ␤-oxidation, and the rate-limiting step is -hydroxylation by cytochrome P450 (CYP) 4F (10,22).…”

Section: Resultsmentioning

confidence: 99%

Dietary Sesame Seed Decreases Urinary Excretion of .ALPHA.- and .GAMMA.-Tocopherol Metabolites in Rats

Uchida

Ichikawa

Abe

et al. 2007

J Nutr Sci Vitaminol

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SummaryWe previously showed that dietary sesame seed and its lignan inhibited ␥ -tocopherol metabolism to 2,7,8-trimethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␥ -CEHC), a ␥ -tocopherol metabolite, and markedly elevated tissue ␥ -tocopherol concentration in rats. The aim of this study was to clarify the effect of dietary sesame seed on ␣ -tocopherol metabolism. Vitamin E-deficient rats fed a vitamin E-free diet for 4 wk were fed a diet containing ␣ -tocopherol, ␣ -and ␥ -tocopherol, or ␣ -tocopherol with sesame seed for 7 d. Urinary excretion of 2,5,7,8-tetramethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␣ -CEHC), a ␣ -tocopherol metabolite, in rats fed ␣ -tocopherol with sesame seed was inhibited ( p Ͻ 0.05) as compared with that in rats fed ␣ -tocopherol alone, or ␣ -and ␥ -tocopherol. The ␥ -CEHC excretion was also less ( p Ͻ 0.05) in rats fed ␣ -tocopherol with sesame seed than that in rats fed ␣ -and ␥ -tocopherol. The inhibition of ␣ -and ␥ -CEHC excretion by sesame seed was accompanied by elevation ( p Ͻ 0.05) of the ␣ -and ␥ -tocopherol concentration in the liver. These results suggest that dietary sesame seed inhibits not only ␥ -tocopherol metabolism to ␥ -CEHC but also ␣ -tocopherol metabolism to ␣ -CEHC in rats. Key Words rats, sesame seed, tocopherol, vitamin E Vitamin E is a potent fat-soluble antioxidant that inhibits lipid peroxidation in biological membranes. In nature, compounds with vitamin E activity are ␣ -, ␤ -, ␥ -or ␦ -tocopherols and ␣ -, ␤ -, ␥ -or ␦ -tocotrienols. Dietary sesame seed or its lignans, such as sesamin and sesaminol, markedly elevate ␥ -tocopherol concentration in rat plasma and tissues ( 1 ). The elevation of the ␥ -tocopherol concentration by sesame lignan is accompanied by inhibition of urinary excretion of 2,7,8-trimethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␥ -CEHC), a ␥ -tocopherol metabolite ( 2 ). In addition to the animal studies, several reports showed that the dietary sesame seed or sesame oil elevated plasma (serum) ␥ -tocopherol concentration in humans ( 3-5 ). Frank et al. ( 6 ) recently reported that consumption of sesame oil muffins significantly decreased the urinary excretion of ␥ -CEHC in humans. Therefore, sesame lignan elevates the ␥ -tocopherol concentration in the serum and tissues by inhibiting ␥ -tocopherol metabolism to ␥ -CEHC in humans and rats.Despite our daily intake of relatively large amount of ␥ -tocopherol, the ␣ -tocopherol concentration in the serum and tissues is much higher than the ␥ -tocopherol concentration because of the discrimination of vitamin E isoforms by ␣ -tocopherol transfer protein ( ␣ -TTP) in the liver. Thus, ␣ -tocopherol is the most biologically active form of vitamin E and inhibits lipid peroxidation of membranes. Sesame seed or its lignan also elevates the ␣ -tocopherol concentration in the serum and tissues of rats ( 7-9 ), or the plasma ratio of ␣ -tocopherol to total cholesterol in human ( 5 ). Sesamin clearly inhibits the production of not only ␥ -CHEC but also 2,5,7,8-tetramethyl-2(2 ′ -carboxyethyl)-6-hy...

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Section: Resultsmentioning

confidence: 99%

Dietary Sesame Seed Decreases Urinary Excretion of .ALPHA.- and .GAMMA.-Tocopherol Metabolites in Rats

Uchida

Ichikawa

Abe

et al. 2007

J Nutr Sci Vitaminol

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“…The initial step of ␣-tocopherol degradation is a w-hydroxylation of the side chain element by cytochrome P450 hydroxylases. 54,55 Supplementation with ␣-tocopherol increases cytochrome P450s levels in mice 12,56 and activates the nuclear pregnane X receptor, 57 which itself regulates many genes linked to xenobiotic detoxification, including several P450 enzymes. 58 It is feasible that ␣-tocopherol is initially metabolized as a xenobiotic, perhaps explaining why previous studies generally only observe a life span extension when supplementation is initiated early in life.…”

Section: Discussionmentioning

confidence: 99%

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

Selman

McLaren

Mayer

et al. 2008

Rejuvenation Research

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. (2008) Lifelongα-tocopherol supplementation increases the median life span of C57BL/6 mice in the cold but has only minor effects on oxidative damage. Rejuvenation Research, 11 (1 ABSTRACTThe effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 ؎ 2°C and supplemented their diet with ␣-tocopherol from 4 months of age. Supplementation significantly increased (p ‫؍‬ 0.042) median life span by 15% (785 days, n ‫؍‬ 44) relative to unsupplemented controls (682 days, n ‫؍‬ 43) and also increased maximum life span (oldest 10%, p ‫؍‬ 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that ␣-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of ␣-tocopherol. We propose that the life span extension observed following ␣-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following ␣-tocopherol supplementation. 83

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“…Apart from these, there are further contradictory findings. Parker et al [171] emphasized that the hypothesis of involvement of CYP3A4 in the metabolism of vitamin E is only based on the assumption of ketoconazole specificity, which proved incorrect [172] . Testing recombinant human CYP3A4 in insect cell derived microsomes revealed no activity towards α-or γ-TOH [140] , whereas a systematic screening of other CYP enzymes showed tocopherol-ω-hydroxylase activity only for CYP4F2 [171] (for further details, see the section on CYP4F2 in chapter "metabolism of vitamin E").…”

Section: Cyp3a4mentioning

confidence: 99%

“…Parker et al [171] emphasized that the hypothesis of involvement of CYP3A4 in the metabolism of vitamin E is only based on the assumption of ketoconazole specificity, which proved incorrect [172] . Testing recombinant human CYP3A4 in insect cell derived microsomes revealed no activity towards α-or γ-TOH [140] , whereas a systematic screening of other CYP enzymes showed tocopherol-ω-hydroxylase activity only for CYP4F2 [171] (for further details, see the section on CYP4F2 in chapter "metabolism of vitamin E"). In addition, Birringer et al [120] showed that production of γ-CEHC from γ-TOH was not affected by rifampicin in HepG2 cells, leading to the conclusion that either CYP3A4 may not degrade all vitamin E forms to the same extent or other CYP enzymes may be involved in γ-TOH metabolism.…”

Section: Cyp3a4mentioning

confidence: 99%

“…Parker et al [171] published a hypothesis to explain the underlying physiological importance of the different rates of metabolism and elimination of the different forms of vitamin E. When murine macrophages (RAW264.7 cells) were incubated with α-TOH, γ-TOH, δ-TOH or δ-T3, different cell viabilities were found: Cell viability for α-TOH was not impaired but was intermediately reduced for γ-TOH and cell viabilities for δ-TOH or δ-T3…”

Section: Kinetics Of Vitamin E Degradationmentioning

confidence: 99%

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Complexity of vitamin E metabolism

Schmölz¹,

Birringer²,

Lorkowski³

et al. 2016

WJBC

175

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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Discovery, Characterization, and Significance of the Cytochrome P450 ω‐Hydroxylase Pathway of Vitamin E Catabolism

Cited by 51 publications

References 13 publications

Dietary Sesame Seed Decreases Urinary Excretion of .ALPHA.- and .GAMMA.-Tocopherol Metabolites in Rats

Dietary Sesame Seed Decreases Urinary Excretion of .ALPHA.- and .GAMMA.-Tocopherol Metabolites in Rats

Lifelongα-Tocopherol Supplementation Increases the Median Life Span of C57BL/6 Mice in the Cold but Has Only Minor Effects on Oxidative Damage

Complexity of vitamin E metabolism

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