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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; /-tocopherol, 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-(/3-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
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