Absorption Metabolism and Excretion

Because of its hydrophobicity, vitamin E requires special transport mechanisms in the aqueous environment of plasma, body fluids, and cells. In humans, vitamin E is taken up in the proximal part of the intestine depending on the amount of food lipids, bile, and pancreatic esterases that are present. It is emulsified together with the fat-soluble components of food. Lipolysis and emulsification of the formed lipid droplets then lead to the spontaneous formation of mixed micelles, which are absorbed at the brush border membrane of the mucosa by passive diffusion. Both a- and 7-tocopherol and dietary fat are taken up without preference by the intestine and secreted in chylo-micron particles together with triacylglycerol and cholesterol (Figure 2). The nearly identical incorporation of a- and 7-tocopherol in chylomicrons after supplementation with equal amounts of the two tocopherols indicates that their absorption is not selective (Figure 2). The chylomicrons are stored as secretory granula and eventually excreted by exocytosis to the lymphatic compartment, from which they reach the bloodstream via the ductus thoracicus. The exchange between the apolipoproteins of the chylomicrons (types AI, AII, and B48) and high-density lipoprotein (HDL) (types C and E) triggers the intravascular degradation of the chylomicrons to remnants by the endothelial lipoprotein lipase (LPL) and is a prerequisite for the hepatic uptake of tocopherols (Figure 2). During LPL-mediated catabolism of chylomicron particles, some of the chylomicron-bound vitamin E appears to be transported and transferred to peripheral tissues, such as muscle, adipose, and brain (Figure 2). The formation of remnants favors the rapid uptake of the tocopherols via the hepatic receptors for apo-E and apo-B.

The chylomicron remnants are subsequently taken up by the liver, where a-tocopherol is preferentially

Chylomicron

Chylomicron

Chylomicron remnants

To peripheral tissues

Chylomicron remnants

0 7-CEHC

Kidney

0 7-CEHC

Kidney

Urinary excretion

Peripheral Tissue Plasma

TAPs?

Membrane compartments

Figure 2 Absorption, transport, and metabolism of a-tocopherol (a-T) and 7-tocopherol (7-T) in peripheral tissues. 1: Both a-T and 7-T are absorbed without preference by the intestine along with lipid and reassembled into chylomicrons. 2: Exchange between apolipoproteins of the chylomicrons (types AI, AII, and B48) and high-density lipoprotein (HDL) (types C and E) occurs. 3: Chylomicrons are degraded to remnants by lipoprotein lipase (LPL) and some a-T and 7-T are transported to peripheral tissues. 4: The resulting chylomicron remnants are then taken up by the liver. 5: In the liver, most of the remaining a-T, but only a small fraction of 7-T, is reincorporated in nascent very low-density lipoproteins (VLDLs) by a-tocopherol transfer protein (a-TTP). 6: Plasma phospholipid transfer protein (PLTP) facilitates the exchange of tocopherol between HDL and LDL for delivery to tissues. 7: Plasma tocopherols are delivered to tissues by LDL and HDL. 8: Tocopherol-associated proteins (TAPs) probably facilitate intracellular tocopherol transfer between membrane compartments. 9: Substantial amounts of 7-T are degraded by a cytochrome P450-mediated reaction to 2,7,8-trimethyl-2-(^-carboxyethyl-6-hydroxychroman (7-CEHC). 10: 7-CEHC is excreted into urine. Adapted from Azzi A and Stocker A (2000) Vitamin E: Non-antioxidant roles. Progress in Lipid Research 39: 231-255; and from Jiang Q, Christen S, Shigenaga MK and Ames BN (2001) 7-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. American Journal of Clinical Nutrition 74: 714-722.

incorporated into nascent very low-density lipo-protein (VLDL) by a specific 32-kDa a-tocopherol transfer protein (a-TTP), which enables further distribution of a-tocopherol to peripheral cells (Figure 2). a-TTP is mainly expressed in the liver, in some parts of the brain, in the retina, in low amounts in fibroblasts, and in the placenta. a-TTP possesses stereospecificity as well as regiospecificity toward the most abundant isomer of vitamin E, (RRR)-a-tocopherol. The sorting process does not tolerate alteration at C2. As a consequence of the selective transfer mechanism, major parts of the natural homologs and nonnatural isomers of a-toco-pherol are excluded from the plasma and secreted with the bile. Relative affinities of tocopherols for a-TTP are as follows: a-tocopherol, 100; ft-toco-pherol, 38; 7-tocopherol, 9; and ¿-tocopherol, 2. A 75-kDa plasma phospholipid transfer protein (PLTP), which is known to catalyze the exchange of phospholipids and other amphipatic compounds between lipid structures, has been shown to facilitate the exchange of a-tocopherol from VLDL to HDL and LDL for further delivery to tissues (Figure 2).

A family of cellular tocopherol-associated proteins (TAPs) with the ability to bind and redistribute a-tocopherol has been identified. TAPs bind to a-tocopherol but not to other isomers of tocopherol. Present in all cells, TAPs may be specifically involved in intracellular a-tocopherol movement, for example, between membrane compartments and plasma membranes, or in optimizing the a-tocopherol content of membranes.

7-Tocopherol appears to be mainly degraded to its hydrophilic 3'-carboxychromanol metabolite, 2,7,8-trimethyl-2-(/-carboxyethyl)-6-hydroxychroman (7-CEHC) (Figure 3), and excreted in the urine. The mechanism of 7-tocopherol metabolism involves terminal cytochrome P450 (CYP)-mediated !-hydroxylation of the tocopherol phytyl side chain, oxidation to the corresponding terminal car-boxylic acid, and sequential removal of two- or three-carbon moieties by /-oxidation, ultimately yielding the hydrophilic 3'-carboxychromanol metabolite of the parent tocopherol that is excreted in the urine. Functional analysis of several recombinant human liver P450 enzymes revealed that tocopherol !-hydroxylase activity was associated only with the cytochrome P450 isoform 4F2 (CYP4F2). Kinetic analysis of the tocopherol ^-hydroxylase activity in recombinant human CYP4F2 microsomal systems revealed similar Km values (37 and 21 mM) but notably different Vmax values (1.99 vs 0.16nmol/nmol of P450/min) for 7- and a-tocopherol, respectively. The data suggest a role for the CYP-mediated !-hydro-xylase pathway in the preferential physiological retention of a-tocopherol and elimination of 7-toco-pherol. In nonsupplemented individuals, a

«-CEHC

7-CEHC

Figure 3 Chemical structures of 2,5,7,8-tetramethyl-2-(/-carboxyethyl)-6-hydroxychroman(a-CEHC) and 2,7,8-trimethyl-2-(/-carboxyethyl)-6-hydroxychroman (7-CEHC).

7-CEHC

Figure 3 Chemical structures of 2,5,7,8-tetramethyl-2-(/-carboxyethyl)-6-hydroxychroman(a-CEHC) and 2,7,8-trimethyl-2-(/-carboxyethyl)-6-hydroxychroman (7-CEHC).

substantial proportion of the estimated daily intake of 7-tocopherol is excreted in human urine as its 7-CEHC metabolite, but a much smaller proportion of a-tocopherol is excreted as 2,5,7,8-tetramethyl-2-(/-carboxyethyl)-6-hydroxychroman (a-CEHC) (Figure 3). a-CEHC is excreted in large amounts only when the daily intake of a-tocopherol exceeds 150 mg or plasma concentrations of a-tocopherol are above a threshold of 30-40 mmol l_1. Even then, urinary excretion of a-CEHC is lower than that of 7-CEHC.

It is likely that it is the capacity of a-TTP rather than the plasma a-tocopherol concentration that determines a-tocopherol degradation. Overall, hepatic catabolism of 7-tocopherol appears to be responsible for the relatively low preservation of 7-tocopherol in plasma and tissues, whereas a-TTP-mediated a-tocopherol transfer plays a key role in the preferential enrichment of a-tocopherol in most tissues. Supplementation with a-tocopherol depletes plasma and tissue 7-tocopherol levels. This is likely due to the preferential affinity of a-TTP for a-tocopherol. However, the depletion of 7-tocopherol may also occur because an increase in a-tocopherol may further reduce the incorporation of 7-tocopherol into VLDL, which leaves more 7-tocopherol to be degraded by CYP. On the other hand, 7-tocopherol supplementation may spare a-tocopherol from being degraded.

Plasma (RRR)-a-tocopherol incorporation is a saturable process. Plasma concentrations of a-tocopherol reach a threshold of 30-40 mmoll-1 despite supplementation with high levels (400 mg or greater) of (RRR)-a-tocopherol. Dose-response studies showed that the limitation in plasma a-tocopherol concentration appears to be a result of rapid replacement of circulating with newly absorbed a-tocopherol. Kinetic analysis has shown that the entire plasma pool of a-tocopherol is replaced daily. The highest concentrations of a-tocopherol in the body are in adipose tissues and adrenal glands. Adipose tissues are also a major store of the vitamin, followed by liver and skeletal muscle. The rate of uptake and turnover of a-tocopherol by different tissues varies greatly. Uptake is most rapid into lungs, liver, spleen, kidney, and red cells (in rats, t1=2 < 15 days) and slowest in brain, adipose tissues, and spinal cord (t1/2 < 30 days). Likewise, depletion of a-tocopherol from plasma and liver during times of dietary deficiency is rapid, whereas adipose tissue, brain, spinal cord, and neural tissues are much more difficult to deplete.

The major route for the elimination of tocopherol from the body is via the feces. Fecal tocopherol arises from incomplete absorption, secretion from mucosal cells, and biliary excretion. Excess a-tocopherol as well as forms of vitamin E not preferentially used, such as synthetic racemic isomer mixtures, or 7-tocopherol are eliminated during the process of nascent VLDL secretion in the liver and are probably excreted into bile. In addition to the urinary excretion of 7-tocopherol as 7-CEHC, biliary excretion is an alternative route for elimination of excess 7-tocopherol. This is confirmed by the fact that the ratio of 7- to a-tocopherol in bile is sevenfold higher than in plasma.

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