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OCR for page 74
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
OCR for page 75
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
OCR for page 76
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.
Representative terms from entire chapter:
single dose
