不同形式的维生素E在体内的药理作用及代谢分析a. StructureVitamin E was discovered in 1922 in green leafy vegetables.1 It is the collection of 8 different molecules (tocopherols and tocotrienols), each contains a chromanol ring system and a side-chain of 16-carbon. These compounds vary in the number and position of methyl groups on the chromanol ring: alpha;- is trimethylated, beta;- and gamma;- are dimethylated, and delta;- is monomethylated.2,3 (Figure 1) The side-chain of tocophrols is saturated, while tocotrienols have double bonds at 3, 7 and 11positions of the side chain.b. Resources and dietaryVitamin E is an essential, fat soluable nutrient that must be provided by foods and supplements because human body cannot synthesize it. Rich dietary sources of vitamin E are edible vegetable oils such as corn oil, soybean and nuts.4 Most oils contain varying amounts of the tocopherols; few contain tocotrienols.2 Tocopherols, as the main form of vitamin E family have been studied more extensively than tocotrienols. gamma;-Tocopherol is most abundant in the US diet4，estimated to be consumed in quantities 3-5 times more than alpha;-tocopherol, however alpha;-tocopherol has the highest blood levels over other tocopherols. Although alpha;-, beta;-, delta;- and gamma;- tocopherols and tocotrienols have similar chemical structure, numerous investigations have clearly demonstrated that individual forms within each subgroup display significant differences in their biological activities and potential health benefits. 1c. Antioxidant and cancer prevention effectTocopherols serve as potent antioxidants by directly preventing the propagation of peroxyl radical reactions. In addition, tocopherols and their metbolites may activate Nrf2 (NF-E2-related factor-2-related antioxidants enzymes) as indirect antioxidants (R). Since alpha;-tocopherol has the highest blood levels over other vitamin E forms，most of the previous studies have concentrated on alpha;-T. Studies already show alpha;-tocopherol induces calnexin in renal tubular cells: another protective mechanism against free radical-induced cellular damage5, and alpha;-tocopheryl phosphate havs uptake, hydrolysis, and antioxidant action in cultured cells and mouse6. The results of most animal and human studies with alpha;-T supplementation have not yield supportive evidence. When gamma;-T is given to human and animals with adequate vitamin E nutrition，the cancer preventative effects have been demonstrated(R). The possiblemechanisms of cancer prevention including the trapping of reactive nitrogen species, inhibition of COX-2 activity, activation of PPAR-gamma; and suppression of inflammation.7 gamma;-TmT（gamma;-tocopherol-rich mixture of tocopherols, containing 57% gamma;-t, 24% delta;-T, 13% alpha;-T and 0.5% beta;-T） at ratios similar to those in our diet , has been demonstrated to inhibit colon, mammary, prostate and lung in rodent models.7A recent study about different forms in inhibiting lung tumorigenesis in vivo showed the activity following the order delta;-T gt; gamma;-TmTgt; gamma;-Tgt;alpha;-T.3 Another study on inhibiting colon cancer cell growth, and cancer cell colony formation and on the induction of apoptosis, showed that the activity followed the ranking order of delta;-T gt; gamma;-Tgt;alpha;-T.8 d. Absorption, distribution and metabolismThe absorption of vitamin E is along with fats, into intestinal cells and incorporated in chylomicrons for secretion to lymph. (Add more details here to describe it) Vitamin E is transported nonspecifically in all of the lipoproteins. Once reach liver, alpha;-T selectively secreted into plasma by alpha;-TTP (alpha;-Tocopherol Transport protein. Thus the liver, not intestine discriminates between tocopherols.2The major metabolites of tocopherols are side-chain degradation initiated by omega;-oxidation and beta;-oxidation, mediated by cytochrome P450 4F（CYP4F）,CYP3A and CYP2B.9 The final products are carboxy-ethyl hydroxychromans (CEHCs) and their precursors, carboxymethylbutyl hydroxychromans (CMBHCs)10 (Figure2); these products are then subjected to glucuronidation and sulfation followed by urinary excretion2. This pathway is responsible for the generation of the major urinary metabolites detected in healthy individuals. 11 Analysis of multiple metabolites of tocopherols and tocotrienols help us to gain the information about bioactivities, distribution and interference of vitamin E.12 The methodology for the determination of tocopherols and short chain metabolites by HPLC-ECD has been set in our laboratory13, and Jiang Qings recent studies, identification and quatification of long chain metabolites like 11-COOH and 13-COOH in vivo and in vitro by HPLC-fluorescence and LC-MS developed the discovery of novel metabolites.14,15 In addition, analysis in human and animal serum, urine, tissues such as liver, small intestine, lung, colon, spleen, heart, mammary and brain after a short time diet of gamma;-TmT has been done in our laboratory. From our earlier studies, the distribution and changes of concentration of tocopherols and multiple metabolites in human and mice have been observed, the variation tendency of concentration rises with the accumulation of time, both in the first few hours, days, and weeks. The results of tissues level suggest the high distribution of tocopherols and tocotrienols in small intestine and liver, less in colon and brain in the first few days of diet. However, the metabolites CEHC and CMBHC accumulate most in small intestine, liver, kidney, pancreas and colon, which may indicate the relationship of cancer prevention effect in these different types of cancer. This inspired us to develop the research in metabolism to explore the distribution，accumulation ，excretion for longer time diet of gamma;-TmT.e. Rational for present workSo far, the methodology to identify and quantify tocoperols and their metabolites has been well developed. alpha;-Tocopherol in serum incorporatd with internal standard has been measured by high-performance liquid chromatography with diode array detector and fluorescence detector16. Multiple metabolites of tocopherols and tocotrienols in mice and human, including CEHC, CMBHC, CDMOHC, CDMDHC and carboxyl tocoferol have been identified by HPLC/electrochemical detection and mass spectrometry13. Tocotrienols and tocopherols have been quantified at the same time with HPLC- UV/VIS detector in cells, animal plasma and intestinal perfusion17. Distribution of tocopherols and tocotrienols in different tissues including serum, liver, kidney, adrenal gland, aorta, muscle, perirenal adipose tissue, apididymal fat and brain were discussed in Tomono Uchidas paper12. In the recent years some novel vitamin E metabolites, long-chain metabolites including 9-COOH, 11-COOH, 13-COOH and 13-OH have been discovered and quantified by LC-MS and HPLC fluorescence. f. Purpose of Our study Our study here attempts to elucidate patterns in tocopherol accumulation in the blood, urine, liver, kidney, lung and feces of C57BL/6J mice following dietary supplementation with 0.3% gamma;-TmT over the course of 63 days. In addition, we detected both the long-chain and short chain metabolites to explore the absorption, bioactivity, metabolism and excretion of their parent compounds.
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