Tissue Uptake of Vitamin

Ascorbate and dehydroascorbate are taken up into tissues by separate mechanisms, and there is litde or no competition between them (Welch et al., 1995)  

Ascorbate enters cells byway of sodium-dependent transporters. 

Dehydroascorbate enters cells byway of the (insulin-dependent) glucose transporters (GLUT), and is reduced to ascorbate intracellularly. 

With cells in culture, high concentrations of flavonoids (Section 14.7.2) inhibit the uptake of both ascorbate and dehydroascorbate, although it is not clear whether inhibitory concentrations of flavonoids occur in vivo (Park and Levine, 2000). 

About 70% of blood ascorbate is in plasma and erythrocytes (which do not concentrate the vitamin from plasma). The remainder is in white cells, which have a marked ability to concentrate ascorbate mononuclear leukocytes achieve 80-fold, platelets 40-fold, and granulocytes 25-fold concentration, compared with plasma concentration. In adequately nourished subjects, and those receiving supplements, the ascorbate concentration in erythrocytes, platelets, and granulocytes, but not in mononuclear leukocytes, is correlated with plasma concentration. Mononuclear leukocytes concentrate ascorbate independendy of plasma concentration (Evans et al., 1982). In deficiency, as plasma concentrations of ascorbate fall, mononuclear leukocyte, granulocyte, and platelet concentrations of ascorbate are protected to a considerable extent. As discussed in Section 13.5.2, the leukocyte content of ascorbate is used as an index ofvitamin C nutritional status, but in view of the differing capacity of different cell types to accumulate the vitamin, differential white cell counts are essential to interpret the results. 

There is no specific storage organ for ascorbate apart from leukocytes (which account for only 10% of total blood ascorbate), the only tissues showing a significant concentration of the vitamin eue the adrenal and pituitmy glemds. Although the concentration of ascorbate in muscle is relatively low, skeletal muscle contains much of the body pool of 5 to 8.5 mmol (900 to 1,500 mg) of ascorbate. 

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Because vitamin E is transported in lipoproteins secreted hy the liver, the plasma concentration depends to a great extent on total plasma lipids. Erythrocytes may also he important in transport, because there is a relatively large amount of the vitamin in erythrocyte membranes, and this is in rapid equilibrium with plasma vitamin E. There are two mechanisms for tissue uptake of the vitamin. Lipoprotein lipase releases the vitamin by hydrolyzing the tri-acylglycerol in chylomicrons and VLDL, whereas separately there is receptor-mediated uptake of LDL-bound vitamin E. Studies in knockout mice suggest that the main mechanism for tissue uptake of vitamin E from plasma lipoproteins is byway of the class B scavenger receptor (Mardones et al., 2002). 

Tissue uptake of vitamin Be is again by carrier-mediated diffusion of pyridoxal (and other unphosphorylated vitamers), followed by metabolic trapping by phosphorylation. Circulating pyridoxal and pyridoxamine phosphates are hydrolyzed by extracellular alkaline phosphatase. All tissues have pyridoxine kinase activity, but pyridoxine phosphate oxidase is found mainly in the liver, kidney, and brain. 

There are two mechanisms for tissue uptake of vitamin E. Lipoprotein lipase releases the vitamin by hydrolysing the triacylglycerols in chylomicrons and VLDL, while separately there is uptake of LDL-bound vitamin E by means of LDL receptors. Retention within tissues depends on binding proteins, and it is likely that the differences in biological activity of the vitamers are due to differential protein binding. y-Tocopherol and a-tocotrienol bind relatively poorly, whereas 5 i i -a-tocopherol and RRR-a-tocopherol acetate do not bind to liver tocopherol-binding protein to any significant extent. 

Vitamin E, like neutral lipids, requires apoB lipoproteins at every stage of its transport (Fig. 27-2). Dietary vitamin E becomes emulsified in micelles produced during the digestive phase of lipid absorption and permeates the intestinal epithelium, similar to fatty acids and cholesterol. Uptake of vitamin E by enterocytes appears to be concentration dependent. Within intestinal cells, vitamin E is packaged into chylomicrons and secreted into lymph. During blood circulation of chylomicrons, some vitamin E may be released to the tissues as a consequence of partial lipolysis of these particles by endothelial cell-anchored lipoprotein lipase. The rest remains associated with chylomicron remnants. Remnant particles are mainly endocy-tosed by the liver and degraded, resulting in the release of fat-soluble vitamins. 

Thiamin that is not bound to plasma proteins is rapidly filtered at the glomerulus. Diuresis increases the excretion of the vitamin, and patients who are treated with diuretics are potentially at risk of thiamin deficiency. Some of the diuretics used in the treatment of hypertension may also inhibit cardiac (and other tissue) uptake of thiamin, thus further impairing thiamin status, which may be a factor in the etiology of heart failure (Suter and Vetter, 2000). 

Intestinal bacteria synthesize riboflavin, and fecal losses of the vitamin may be five- to six-fold higher than intake. It is possible that bacterial synthesis makes a significant contribution to riboflavin intake, because there is carrier-mediated uptake of riboflavin into colonocytes in culture. The activity of the carrier is increased in riboflavin deficiency and decreased when the cells are cultured in the presence of high concentrations of riboflavin. The same carrier mechanism seems to be involved in tissue uptake of riboflavin (Said et al., 2000). 

Absorption, transport, and cellular uptake of vitamin B12 in humans. IF, Intrinsic factor TCII, transcobalamin II circles in the membranes of the ileal mucosal cell and peripheral tissues represent transport molecules for IF/B12 and TCII/B12. respectively. 

Theoretically, when blood and liver levels of vitamin A are reduced as in alcoholic hepatitis and alcoholic cirrhosis, subjects should receive supplemental vitamin A. Such supplementation, as high as 3000-10,(X)0 xg daily, has been shown to correct abnormal dark adaptation in some alcoholic cirrhotics uncomplicated by zinc deficiency (Morrison et aL, 1978 Russell et aL, 1978 Mobarhan et aL, 1981). Some studies in rats, however, indicate that acute and chronic administration of ethanol impairs hepatic and/or peripheral tissue uptake of newly ingested retinyl ester and/or causes the release of retinyl esters from hepatic tissue... 

In plasma, vitamin B circulates bound to transcobalamin I, which is required for tissue uptake of the vitamin, and transcobalamin II, which seems to be a storage form of the vitamin. 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

Parathyroidectomy is a treatment of last resort for sHPT, but should be considered in patients with persistently elevated iPTH levels above 800 pg/mL (800 ng/L) that is refractory to medical therapy to lower serum calcium and/or phosphorus levels.39 A portion or all of the parathyroid tissue may be removed, and in some cases a portion of the parathyroid tissue may be transplanted into another site, usually the forearm. Bone turnover can be disrupted in patients undergoing parathyroidectomy whereby bone production outweighs bone resorption. The syndrome, known as hungry bone syndrome, is characterized by excessive uptake of calcium, phosphorus, and magnesium for bone production, leading to hypocalcemia, hypophosphatemia, and hypomagnesemia. Serum ionized calcium levels should be monitored frequently (every 4 to 6 hours for the first 48 to 72 hours) in patients receiving a parathyroidectomy. Calcium supplementation is usually necessary, administered IV initially, then orally (with vitamin D supplementation) once normal calcium levels are attained for several weeks to months after the procedure. 

Figure 15.13 The roles of different tissues in production of the active form of vitamin D. Two major effects of vitamin D are presented release of calcium from bone and uptake of calcium from the intestine.

Vitamin B12 (cyanocobalamin) is produced by bacteria B12 generated in the colon, however, is unavailable for absorption (see below). liver, meat, fish, and milk products are rich sources of the vitamin. The minimal requirement is about 1 pg/d. Enteral absorption of vitamin B 2 requires so-called intrinsic factor from parietal cells of the stomach. The complex formed with this glycoprotein undergoes endocytosis in the ileum. Bound to its transport protein, transcobalamin, vitamin B12 is destined for storage in the liver or uptake into tissues. 

The absorption of vitamin C is saturated at high doses, and therefore intakes above 1 g/day would be associated with negligible increased uptake at tissue levels, but they increase the risk of adverse gastrointestinal effects. Indeed, acute gastrointestinal intolerance (e.g., abdominal distension, flatulence, diarrhea, transient colic) has been observed. 

The nutritional value of a food commodity or diet with respect to a particular vitamin may be expressed in terms of the vitamin s bioavailability, which refers to the proportion of the quantity of vitamin ingested that undergoes intestinal absorption and utilization by the body. Utilization encompasses transport of the absorbed vitamin to the tissues, cellular uptake, and conversion to a form that can fulfill some biochemical or physiological function, either immediately or after storage. 

The vitamin D metabolites (l,25(OH)2D3 and 24,25(OH)2D3) are also known to exert an effect upon cartilage [33]. Receptors for both dihydroxylated vitamin D metabolites have been apparently found in this tissue, and they both can stimulate the uptake of 35S04 into proteoglycans. 

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