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vitaniin B12 Vitamin BE (cobalamin) is unique among vitamins in that it is synthesized in nature only by microorganisms. It is the last vitamin to have been discovered (in the late 1940s) and is the most potent on a weight basis. Vitamin BE deficiencies are characterized by a wide variety of signs in various animal species. The natural concentra- tions of this vitamin in feeds are generally low. A syn- thetic form is commonly used as a feed supplement. NUTRITIONAL ROLE Dietary Requirements of Various Species All nonruminant species require dietary sources of vitamin Bit. The required amounts are low because of the presence of microbial sources of the vitamin in the environment (e.g., manure) and bacterial synthesis in the gastrointestinal tract. However, the latter contribu- tion may be of questionable significance. Supplementa- tion of diets based solely on plant feedstuffs is essential. Vitamin B~2-deficient swine may show macrocytic hyperchromic anemia, neuropathies, reproductive fail- ures, and dermatitis; chickens may show abnormal feathering; and rats may show porphyrin-caked whisk- ers. The estimated requirements of most species for vitamin BE range from 9 to 22 ,ug/kg of diet. Biochemical Functions Vitamin BE normally occurs in feeds bound to protein in the methyl or 5'-deoxyadenosyl forms, each of which is known to be a coenzyme in only a single reaction in animal metabolism. The methyl form (methyl cobala- min) is required as a carrier of the methyl group from N6-methyltetrahydrofolate to homocysteine in the conversion of the latter to methionine. The 5'- deoxyadenosyl form (adenosylcobalamin) is required in the conversion of methylmalonyl CoA to succinyl CoA, an important step in the metabolism of propionic acid. FORMS OF THE VITAMIN The structure of vitamin BE is shown in Figure 17. It consists of a corrin ring system with a central cobalt atom. Cyanocobalamin is the usual form of the vitamin used in supplementing animal feeds. It contains a cya- nide group as an artifact of the preparation process at- tached to the central cobalt atom. Little, if any, of this form is believed to occur naturally. However, other forms of the vitamin in which cyanide is replaced by another group occur naturally. These include hydroxy- cobalamin that has been isolated from liver and nitrito- cobalamin that has been isolated from microorganisms. Other forms, which are found commonly in feeds, are methy~cobalamin (the cyanide group replaced with a methyl group) and 5'-deoxyadenosylcobalamin (the cya- nide group replaced with a deoxyadenosylcobalamin group). All of the above-mentioned forms have vitamin BE activity. ABSORPTION AND METABOLISM Vitamin BE is synthesized by the intestinal microflora in nonruminant species and by rumen microbes in rumi- nants. This source is normally sufficient to meet the needs of ruminants. It is not known how much of the source can be absorbed in nonruminants, however. Absorption of this water-soluble vitamin is mainly or exclusively in the ileum and is facilitated by the pres- ence of an intrinsic factor released in gastric juice. Fail- ure to produce the intrinsic factor (for example, as the result of pernicious anemia or total gastrectomy) results in failure to absorb vitamin Bit. Denker (1983) injected pregnant mice with radiolabeled vitamin BE (cyanoco 74

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NH2-CO-CH2-CH2 CH3 CH3/CH2-CO-NH2 NH2-CO-CH2 ACHE -CH2-CO-NH2 NH2-CO-CH2~CH3 fO-CH2-CH2 CH3 CH3 CH2-CH2-CO-NH2 NH CH3 -CH O N ~ CH O OH | l ~ OH-CH2 0 Vitamin B ~ 2 FIGURE 17 Chemical structure of the cyano form of vitamin BE (cyanocobalamin). balamin-57Co) intravenously at a dose rate of 3.2 mg/kg of BW. Three hours later, he recovered 79 percent of the vitamin in the placenta, 1.5 percent in the serum, 2.1 percent in the fetus, 2.3 percent in the liver, and 15 percent in the kidney. With continued intake of the vita- min, animals show tissue storage of cobalamins princi- pally in the liver (30 to 60 percent of the total body load), but also at lower levels in the kidney, heart, spleen, and brain (Ellenbogen, 19841. In humans, the tissue storage TABLE 16 Research Findings of High Levels of Vitamin B12 in Animals Species and Age or Administration No. of Animal Weight 1 d 15 or 30 ~g/kg diet Chickens, leghorns, 1 1-60/group Mice, 2 Mice, albinos, 10/group Amount Duration Route Gestating 0.114 fig 36g Fig 7.5, 15,or30pg Mice, albinos, 11 g 30 fig 10/group Mice, 20 g 100-1,600 mgtkg 3-10/group BW Mice, 3/group 20 g NOTE: The form was BE in all cases. 4 wk Diet 2 injections IV 10 min apart Single dose IP Single dose SC Single dose IP 800 and 1,600 mg/kg Single dose IV BW Vitamin BY 75 of the vitamin is so great that signs of vitamin By defi- ciency may not appear for months or years after the vitamin has stopped being excreted in urine and bile. Vitamin By acts in a number of roles that are impor- tant in the functioning of tetrahydrofolate, which is the facilitation of folate entry into cells and the transfer of the methyl group from methyltetrahydrofolate to homo- cysteine. In By deficiency, tetrahydrofolate is thought to accumulate as methyltetrahydrofolate, which is un- able to transfer methyl groups in the synthesis of thymi- dine. The resulting defect in DNA synthesis, which is characteristic of folate deficiency, also is produced by a By deficiency. Because vitamin By is required in the conversion of propionate to succinate, deficient animals excrete methylmalonic acid in the urine. The criteria for vitamin By adequacy include normal rates of growth, hematopoiesis, reproduction, offspring viability, and liver concentrations of the vitamin. HYPERVITAMINOSIS A summary of the effects of vitamin B12 administra- tion in animals is shown in Table 16. Schaefer et al. (1949) fed 15 or 30 ,ug of vitamin B~2/kg of diet to day-old leghorn chickens to 4 weeks of age and found no adverse effects of the higher level. Traina (1950) administered to mice intraperitoneal doses of 7.5, 15, and 30 fig of vita- min Bit, or a subcutaneous dose of 30 ,ug. Traina ob- served signs of toxicity with doses of 15 fig (1.36 mg/kg of BW) and higher. Winter and Mushett (1951) adminis- tered doses of up to 1,600 mg of vitamin B~2/kg of BW to mice by either the intraperitoneal or intravenous route and reported no adverse effects on growth or survival. Effect Growth rate similar; no adverse effects Concentration greatest in placenta 7.5 fig, no adverse effects; 15 ,ug, 20~o mortality; 30 fig, 100% mortality 100(70 Mortality No mortality or adverse effects on growth No mortality or adverse effects Reference Schaefer et al., 1949 Denker, 1983 Traina, 1950 Traina, 1950 Winter and Mushett, 1951 Winter and Mushett, 1951

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76 Vitamin Tolerance of Animals They suggested that the effects found by Traina (1950) may have been due to the presence of toxic impurities in the sample of vitamin used. PRESUMED UPPER SAFE LEVELS Insufficient data are available to support estimates of the maximum dietary tolerable levels of vitamin Bit. Data from a single chick study suggest that 3 times the vitamin By requirement of that species can be included safely in the diet, however. Mouse data suggest that dietary levels of at least several hundred times the re- quirement are safe. SUMMARY I. Vitamin By is a water-soluble vitamin that is stored principally in the liver. It is required in the diets of non- ruminant animals. 2. Data from mouse studies suggest that vitamin By is innocuous when administered intraperitioneally or in- travenously in relatively high doses and that dietary levels of at least several hundred times the requirement are safe. REFERENCES Denker, L. 1983. Placental accumulation of 57Co-vitamin Bl2 in mice studied by light and electron-microscopic autoradiography. Pla- centa 4:207. Ellenbogen, L.1984. Vitamin Bit. P.497 in Handbook of Vitamins, L. J. Machlin, ed. New York: Marcel Dekker. Schaefer, A. E., W. D. Salmon, and D. R. Strength. 1949. Interrela- tionship of vitamin BE and choline. II. Effect on growth of the chick. Proc. Soc. Exp. Biol. Med. 71:202. Traina, V.1950. Toxicity studies on vitamin BE in albino mice. Arch. Pathol. 49:278. Winter, C. A., and C. W. Mushett.1951. Absence of toxic effects from single injections of crystalline vitamin Bit. J. Am. Pharm. Assoc. 39:360.