Vitamin metabolic activation

The kidneys are located on the posterior part of the abdomen on either side of the spine, below the diaphragm, and behind the liver and stomach. They are bean-shaped and weigh approximately 150 grams (0.33 lb) each. The primary function of the kidneys is excretion. They work to excrete waste products through a series of steps involving glomerular filtration, secretion, and reabsorption. The kidneys also have several endocrine (e.g., production of erythropoietin and renin) and metabolic (e.g., vitamin D activation and drug metabolism) functions. 

On rare occasions an organic aciduria occurs not because of an enzyme deficiency but from a failure to transport or activate a water-soluble vitamin that serves as a cofactor for the reaction in question. Thus, congenital deficiencies in the metabolism of vitamin B12 commonly give rise to methylmalonic aciduria (Fig. 40-1, Table 40-2). Similarly, deficiencies of biotin metabolism can cause a severe organic aciduria (Table 40-2). It is very important to be aware of the defects of vitamin metabolism because the administration of large doses of these cofactors may completely prevent brain damage. 

The enzyme mediating remethylation, 5-methyltetrahy-drofolate-betaine methyltransferase (Fig. 40-4 reaction 4), utilizes methylcobalamin as a cofactor. The kinetics of the reaction favor remethylation. Faulty remethylation can occur secondary to (1) dietary factors, e.g. vitamin B12 deficiency (2) a congenital absence of the apoenzyme (3) a congenital inability to convert folate or B12 to the methylated, metabolically active form (see below) or (4) the presence of a metabolic inhibitor, e.g. an antifolate agent that is used in an antineoplastic regimen. 

The activity of vitamin A is related to vision process, tissue differentiation, growth, reproduction, and the immune system. A deficiency of this micronutrient mainly leads to visual problems, impaired immune function, and growth retardation in children. Hypervitaminosis could lead to hepatotoxicity, affect bone metabolism, disrupt lipid metabolism, and teratogenicity [417]. The isomerization of P-carotene, due to technological processes in foods, leads to a reduction of the vitamin A activity it is therefore important to analyze it. 

The absorption of vitamins K2, which are found mainly in cheese, curd cheese, and natto, is much higher and may be almost complete. Thus the nutritional importance of menaquinones is often underestimated. The vitamin K activity is related to the activation of specific proteins involved in blood clotting and bone metabolism. Clinical vitamin deficiency due to dietary inadequacy is rare or nonexistent in healthy adults, thanks to the widespread distribution of the vitamin K in foodstuffs and the microbiological flora of the gut, which synthesizes menaquinones. Only infants up to 6 months are at risk of bleeding due to a vitamin K deficiency. No data on negative effects of an overdose of vitamin K are found [417]. 

Haloalkanes. Certain haloalkanes and haloalkane-containing mixtures have been demonstrated to potentiate carbon tetrachloride hepatotoxicity. Pretreatment of rats with trichloroethylene (TCE) enhanced carbon tetrachloride-induced hepatotoxicity, and a mixture of nontoxic doses of TCE and carbon tetrachloride elicited moderate to severe liver injury (Pessayre et al. 1982). The researchers believed that the interaction was mediated by TCE itself rather than its metabolites. TCE can also potentiate hepatic damage produced by low (10 ppm) concentrations of carbon tetrachloride in ethanol pretreated rats (Ikatsu and Nakajima 1992). Acetone was a more potent potentiator of carbon tetrachloride hepatotoxicity than was TCE, and acetone pretreatment also enhanced the hepatotoxic response of rats to a TCE-carbon tetrachloride mixture (Charbonneau et al. 1986). The potentiating action of acetone may involve not only increased metabolic activation of TCE and/or carbon tetrachloride, but also possible alteration of the integrity of organelle membranes. Carbon tetrachloride-induced liver necrosis and lipid peroxidation in the rat has been reported to be potentiated by 1,2- dichloroethane in an interaction that does not involve depletion of reduced liver glutathione, and that is prevented by vitamin E (Aragno et al. 1992). 

Pyridoxine (vitamin Be) is essential for protein metabolism and plays an important role in hemoglobin production. Pyridoxamine and pyri-doxal also possess vitamin Be activity. Sources of... 

The primary supply of vitamin in humans is not obtained from the diet but rather is derived from the ultraviolet photoconversion of 7-dehydrocholesterol to vitamin Ds in skin. Thus, vitamin Dj synthesis varies with the seasons. D3 is a prohormone and requires further metabolic conversion to exert biological activity in its target organs (Fig. 66.2). The liver and the kidney are the major sites of metabolic activation of this endogenous sterol hormone. The initial transformation of D3 occurs in the liver and is catalyzed by the enzyme 25-OH-D3-hydroxylase... 

Cholecalciferol is pure vitamin D3 derived from the ultraviolet conversion of 7-dehydrocholesterol to cholecalciferol. Ergocalciferol vitamin D2) is a sterol derived from yeast and fungal ergosterol. Calcitriol [Rocaltrol, 1,25-(0H)2D3] is the metabolically active vitamin D3 compound. Dihydrotachysterol is a synthetic compound that may act somewhat more quickly than either vitamin D2 or D3. 

In 1956 selenium was identified (123) as an essential micronutrient in nutrition. In conjunction with vitamin E, selenium is effective in the prevention of muscular dystrophy in animals. Sodium selenite is administered to prevent exudative diathesis in chicks, a condition in which fluid leaks out of the tissues white muscle disease in sheep and infertility in ewes (see Feed additives). Selenium lessens the incidence of pneumonia in lambs and of premature, weak, and stillborn calves controls hepatosis dietetica in pigs and decreases muscular inflammation in horses. White muscle disease, widespread in sheep and catde of the selenium-deficient areas of New Zealand and the United States, is insignificant in high selenium soil areas. The supplementation of animal feeds with selenium was approved by the U.S. FDA in 1974 (see Feed additives). Much of selenium s metabolic activity results from its involvement in the selenoprotein enzyme, glutathione peroxidase. 

Doxercalciferol, the active ingredient in Hectorol, is a synthetic vitamin D analog that undergoes metabolic activation in vivo to form 1 (alpha),25-dihydroxyvitamin D2 (l(alpha),25-(OH)2D2), anaturally occurring, biologically active form of vitamin D2. Hectorol is available as soft... 

These drugs (e.g., cephaloridine) may be nephrotoxic causing proximal tubular necrosis. Cephaloridine is actively taken up from blood into proximal tubular cells by OAT 1. The drug therefore accumulates in the kidney. Metabolic activation via cytochrome P-450 may be involved. GSH is oxidized, and as NADPH is also depleted, the GSSG cannot be reduced back to GSH. As vitamin E-depleted animals are more susceptible, it has been suggested that lipid peroxidation may be involved. Damage to mitochondria also occurs. 

CYP2E1 is the principal catalyst of vinylidene chloride metabolism and metabolic activation. This conclusion is based on the following findings. Inducers (ethanol, acetone) and inhibitors (diethyldithiocarbamate) increase and decrease, respectively, metabolic activation of vinylidene chloride in mouse liver microsomes and in isolated mouse hepatocytes (Kainz et al., 1993 Lee Forkert, 1994 Dowsley et al., 1995). Vitamin A treatment increases CYP2E1 activity in rat liver microsomes and also potentiates vinylidene chloride toxicity in liver slices from treated animals (Wijeweera et al., 1996). In mouse liver microsomes in vitro, vinylidene chloride decreases CYP2E1 levels (Lee Forkert, 1994). 

THIAMINE (Vitamin Bi). Some earlier designations for this substance included aneurin, antmeuntic factor, antibenben factor, and oryzamin. Thiamine is metabolically active as thiamine pyrophosphate (TPP). the formula of which is ... 

VITAMIN B (Pyridoxine). Infrequently called adermine or pyridoxol, this vitamin participates in protein, carbohydrate, and lipid metabolism. The metabolically active form of B6 is pyridoxal phosphate, the structures of which are ... 

Uptake of Ca2+ from the intestine is stimulated by vitamin D.447 Vitamin D3 is converted to the 25-hydroxy derivative in the liver (equation 11) by a two component mixed-function hydroxylase.448 The metabolically active 1,25-dihydroxy form is synthesized by further hydroxylation in the kidney. This latter stage involves the renal 25-hydroxyvitamin D3- 1-hydroxylase in a reaction which is controlled by Ca2+, parathyroid hormone and phosphate. This renal hydroxylase contains a flavoprotein, an iron-sulfur protein (with an Fe2S2 cluster) and cytochrome P-450.447... 

Lund and DeLuca (101) administered [ H] vitamin D3 to rats and found biologically active metabolites in the bone, liver and serum. The aqueous-soluble metabolites from the tissues and the feces did not have vitamin D activity. At least three biologically active metabolites were isolated from the chloroform-soluble portion of the extract. One of these was found in large amounts in the liver, blood and bone. In 1968, Blunt et. al. (102) proved convincingly that this major metabolite is 25-hydroxyvitamin D3 (25-OH-D3). Two other groups of investigators (103,104) independently found clues to the metabolic hydroxylation of vitamin Do. It was soon established that 25-hydroxylation of vitamin D3 takes place primarily in the liver (105,106) and that 25-0H-D3 is the major form of circulating vitamin D3 in human plasma (107). 

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metabolically active vitamin D hormone results from two successive hydroxylations in the liver at position 25 (- calcifediol) and in the kidney at position 1 (- calcitriol = vitamin D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca2+ and phosphate. Vitamin D hormone promotes enteral absorption and renal reabsorption of Ca2+ and phosphate. As a result of the increased Ca2+ and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vitamin D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic use aims at replacement. Mostly, vitamin D is given in liver disease, calcifediol may be indi-... 

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