The aim of this study was to clarify the contribution of cytochrome P450 (CYP)-dependent metabolism of vitamin E isoforms to their tissue concentrations. We studied the effect of ketoconazole, a potent inhibitor of CYP-dependent vitamin E metabolism in cultured cells, on vitamin E concentration in rats. Vitamin E-deficient rats fed a vitamin E-free diet for 4 weeks were administered by oral gavage a vitamin E-free emulsion, an emulsion containing alpha-tocopherol, gamma-tocopherol or a tocotrienol mixture with or without ketoconazole. Alpha-tocopherol was detected in the serum and various tissues of the vitamin E-deficient rats, but gamma-tocopherol, alpha- and gamma-tocotrienol were not detected. Ketoconazole decreased urinary excretion of 2,5,7,8-tetramethyl-2(2'-carboxyethyl)-6-hydroxychroman after alpha-tocopherol or a tocotrienol mixture administration, and that of 2,7,8-trimethyl-2(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) after gamma-tocopherol or a tocotrienol mixture administration. The gamma-tocopherol, alpha- and gamma-tocotrienol concentrations in the serum and various tissues at 24 h after their administration were elevated by ketoconazole, while the alpha-tocopherol concentration was not affected. The gamma-tocopherol or gamma-tocotrienol concentration in the jejunum at 3 h after each administration was also elevated by ketoconazole. In addition, significant amount of gamma-CEHC was in the jejunum at 3 h after gamma-tocopherol or gamma-tocotrienol administration, and ketoconazole inhibited gamma-tocopherol metabolism to gamma-CEHC in the jejunum. These results showed that CYP-dependent metabolism of gamma-tocopherol and tocotrienol is a critical determinant of their concentrations in the serum and tissues. The data also suggest that some amount of dietary vitamin E isoform is metabolized by a CYP-mediated pathway in the intestine during absorption.

The aim of this study was to evaluate tissue distribution of vitamin E isoforms such as α- and γ-tocotrienol and γ-tocopherol and interference with their tissue accumulation by α-tocopherol. Rats were fed a diet containing a tocotrienol mixture or γ-tocopherol with or without α-tocopherol, or were administered by gavage an emulsion containing tocotrienol mixture or γ-tocopherol with or without α-tocopherol. There were high levels of α-tocotrienol in the adipose tissue and adrenal gland, γ-tocotrienol in the adipose tissue, and γ-tocopherol in the adrenal gland of rats fed tocotrienol mixture or γ-tocopherol for 7 weeks. Dietary α-tocopherol decreased the α-tocotrienol and γ-tocopherol but not γ-tocotrienol concentrations in tissues. In the oral administration study, both tocopherol and tocotrienol quickly accumulated in the adrenal gland; however, their accumulation in adipose tissue was slow. In contrast to the dietary intake, α-tocopherol, which has the highest affinity for α-tocopherol transfer protein (αTTP), inhibited uptake of γ-tocotrienol to tissues including adipose tissue after oral administration, suggesting that the affinities of tocopherol and tocotrienol for αTTP in the liver were the critical determinants of their uptake to peripheral tissues. Vitamin E deficiency for 4 weeks depleted tocopherol and tocotrienol stores in the liver but not in adipose tissue. These results indicate that dietary vitamin E slowly accumulates in adipose tissue but the levels are kept without degradation. The property of adipose tissue as vitamin E store causes adipose tissue-specific accumulation of dietary tocotrienol.

The aim of this experiment was to clarify the contribution of the alpha-tocopherol transfer activity of lipoprotein lipase (LPL) to vitamin E transport to tissues in vivo. We studied the effect of Triton WR1339, which prevents the catabolism of triacylglycerol-rich lipoproteins by LPL on vitamin E distribution in rats. Vitamin E-deficient rats fed a vitamin E-free diet for 4 wk were injected with Triton WR1339 and administered by oral gavage an emulsion containing 10 mg of alpha-tocopherol, 10 mg of gamma-tocopherol, or 29.5 mg of a tocotrienol mixture with 200 mg of sodium taurocholate, 200 mg of triolein, and 50 mg of albumin. alpha-Tocopherol was detected in the serum and other tissues of the vitamin E-deficient rats, but gamma-tocopherol, alpha- and gamma-tocotrienol were not detected. Triton WR1339 injection elevated (P<0.05) the serum alpha-tocopherol concentration and inhibited (P<0.05) the elevation of alpha-tocopherol concentration in the liver, adrenal gland, and spleen due to the oral administration of alpha-tocopherol. Neither alpha-tocopherol administration nor Triton WR1339 injection affected (P>or=0.05) the alpha-tocopherol concentration in the perirenal adipose tissue, epididymal fat, and soleus muscle despite a high expression of LPL in the adipose tissue and muscle. These data show that alpha-tocopherol transfer activity of LPL in adipose tissue and muscle is not important for alpha-tocopherol transport to the tissue after alpha-tocopherol intake or that the amount transferred is small relative to the tissue concentration. Furthermore, Triton WR1339 injection tended to elevate the serum gamma-tocopherol (P=0.071) and alpha-tocotrienol (P=0.053) concentrations and lowered them (P<0.05) in the liver and adrenal gland of rats administered gamma-tocopherol or alpha-tocotrienol. These data suggest that lipolysis of triacylglycerol-rich chylomicron by LPL is necessary for postprandial vitamin E transport to the liver and subsequent transport to the other tissues.

We have shown that intake of sesame seed and its lignan increases vitamin E concentrations and decreases urinary excretion levels of vitamin E metabolites in male Wistar rats, suggesting inhibition of vitamin E catabolism by sesame lignan. The aim of this study was to examine whether dietary sesame seed also increased vitamin K concentrations, because its metabolic pathway is similar to that of vitamin E. To test the effect of sesame lignan on vitamin K concentrations, male Wistar rats were fed a control diet or a diet with 0.2% sesamin (a sesame lignan) for 7 d in experiment 1. Liver phylloquinone (PK), menaquinone-4 (MK-4), and γ-tocopherol were greater in rats fed sesamin than in control rats. To test the effect of sesame seed on vitamin K concentrations, male Wistar rats were fed a control diet or a diet with 1, 5, or 10% sesame seed for 3 d in experiment 2. Liver and kidney PK and γ-tocopherol but not MK-4 were greater in rats fed sesame seed than in control rats, although differences in dietary amounts of sesame seed did not affect the PK concentrations. For further confirmation of the effect of sesame seed, male Wistar rats were fed a control diet or a diet with 20% sesame seed for 40 d in experiment 3. Kidney, heart, lung, testis, and brain PK and brain MK-4 were greater in rats fed sesame seed than in control rats. The present study revealed for the first time, to our knowledge, that dietary sesame seed and sesame lignan increase not only vitamin E but also vitamin K concentrations in rat tissues.

SummaryWe previously found that 2,7,8-trimethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␥ CEHC), a metabolite of the vitamin E isoforms ␥ -tocopherol or ␥ -tocotrienol, accumulated in the rat small intestine. The aim of this study was to evaluate tissue distribution of vitamin E metabolites. A single dose of ␣ -tocopherol, ␥ -tocopherol or a tocotrienol mixture containing ␣ -and ␥ -tocotrienol was orally administered to rats. Total amounts of conjugated and unconjugated metabolites in the tissues were measured by HPLC with an electrochemical detector, and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox) was used as an internal standard. Twenty-four hours later, the vitamin E isoforms were detected in most tissues and in the serum. However, 2,5,7,8-tetramethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␣ CEHC), a metabolite of ␣ -tocopherol or ␣ -tocotrienol, and ␥ CEHC accumulated in the serum and in some tissues including the liver, small intestine and kidney. Administration of ␣ -tocopherol increased the ␥ CEHC concentration in the small intestine, suggesting that ␣ -tocopherol enhances ␥ -tocopherol catabolism. In contrast, ketoconazole, an inhibitor of cytochrome P450 (CYP)-dependent vitamin E catabolism, markedly decreased the ␥ CEHC concentration. These data indicate that vitamin E metabolite accumulates not only in the liver but also in the small intestine and kidney. We conclude that some dietary vitamin E is catabolized to carboxyethyl-hydroxychroman in the small intestine and is secreted into the circulatory system. Key Words carboxyethyl-hydroxychroman, tocopherol, tocotrienol, vitamin E Vitamin E is a fat-soluble antioxidant that inhibits lipid peroxidation in biological membranes. In nature, compounds with vitamin E activity are ␣ -, ␤ -, ␥ -or ␦ -tocopherol and ␣ -, ␤ -, ␥ -or ␦ -tocotrienol. ␣ -and ␥ -tocopherol are abundant in dietary vitamin E while tocotrienol is only present in some plant sources, such as palm oil and rice bran, while daily foods contain low levels of tocotrienol. The dietary vitamin E isoforms are absorbed in the small intestine, secreted with triacylglycerol-rich chylomicrons into the lymph and blood, and then transported to the liver ( 1 , 2 ). The vitamin E isoform ␣ -tocopherol is preferentially incorporated into VLDL and transported to tissues by lipoprotein ( 3 , 4 ) because of its high affinity for ␣ -tocopherol transfer protein ( ␣ TTP) ( 5 ). In contrast, the other vitamin E isoforms, including ␥ -tocopherol and tocotrienol, are catabolized and excreted. Therefore, ␣ -tocopherol has the highest biological activity among vitamin E isoforms.All vitamin E isoforms undergo catabolism to phytyl short-chain carboxyethyl hydroxychromans (CEHC) such as 2,5,7,8-tetramethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␣ CEHC), a metabolite of ␣ -tocopherol and ␣ -tocotrienol, and 2,7,8-trimethyl-2(2 ′ -carboxyethyl)-6-hydroxychroman ( ␥ CEHC), a metabolite of ␥ -tocopherol and ␥ -tocotrienol ( 6-8 ). The catabolic pathway involves -hydroxylation of the phytyl chain and ...