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OCR for page 58
Vitamin Be (Pyndoxine)
The term vitamin B6 is the generic description for the
2-methy~pyridine derivatives that have the biological
activity of pyridoxine (Figure 13~. The vitamin includes
aldehyde (pyridoxal) and amine (pyridoxamine-) forms.
Originally part of Goldberger's "pellagra-preventative
factor," vitamin B6 was recognized to have a specific
role in preventing dermatitic acrodynia in rats. It was
subsequently isolated and identified in the late 1930s.
Vitamin B6 is obtained from both plant and animal
sources. It is also synthesized by the gut microflora,
though in nonruminant animals this source is of doubtful
slgnlilcance.
NUTRITIONAL ROLE
Dietary Requirements of Various Species
Nonruminant animals require a dietary source of pyri-
doxine to prevent the development of several deficiency
signs. These include reduced growth, muscular weak-
ness, hyperirritability, epileptiform convulsions, ane-
mia, acrodynia, scaly dermatitis, and alopecia (NRC,
1978~. Nutritional requirements range from 0.9 to 6 ma/
kg of diet. Protein intake affects vitamin B6 require-
ments. Consequently, requirements are often expressed
in protein intake terms.
Biochemical Functions
The biologically active forms of vitamin B6 are the
coenzymes, pyridoxal phosphate (PLOP) and pyridox-
alamine phosphate (PMP). PLP is involved in most
reactions of amino acid metabolism including trans-
amination, decarboxylation, desulfhydration and non-
oxidative deamination. PLP also has roles in the biosyn-
thesis of porphyrins (as a coenzyme for b-aminolevu
58
linate synthase) and in the catabolism of glycogen (as
part of glycogen phosphorylase). Another role, pres-
ently not understood, is apparent in the metabolism elf
lipids. PLP is important in the metabolism of
y-aminobutyric acid in the brain and in the synthesis of
epinephrine and norepinephrine from either phenylala
· ~
nine or tyroslne.
FORMS OF THE VITAMIN
The predominant dietary form of this vitamin is gen-
erally pyridoxine (PN), which is the main form in plant
products. Pyridoxal (PL) and pyridoxamine are the prin-
cipal forms found in animal tissues. All three forms are
converted in the animal body to the metabolically active
form, PEP. The synthetic form of pyridoxine used for
dietary supplementation is generally pyridoxine hydro-
chloride (PN HCl) although some researchers have
used the free base.
ABSORPTION AND METABOLISM
The rumen microflora synthesize pyridoxine in
amounts normally sufficient to meet the needs of rumi-
nants. Microbial synthesis also occurs in the colons of
nonruminants. Pyridoxine from this source is not ab-
sorbed in appreciable amounts from that organ, how-
ever. Absorption of this water-soluble vitamin occurs in
the small intestine by a passive process. There appears
to be little storage in the botly. Differences have been
reported in the efficiency of absorption and retention of
this vitamin among species. Following an administered
dose of PN, the amount recovered in urine was 50 to 70
percent for the rat (Cox et al., 1962), 20 percent for the
dog (Scud) et al., 1940), and less than 10 percent for
OCR for page 59
Vitamin B6 (Pyridoxine) 59
R
HO :~' CH2 CH2 OH
H3C~N CH3
Vitamin B6 (pyridoxine)
FIGURE 13 General chemical structure of vitamin B6 (pyri-
doxine). The R group may be CH2OH (pyridoxol), CHO (pyri-
doxal), or CH2NH2 (pyridoxamine).
humans (Cohen et al., 19731. Pyridoxine is relatively
more toxic than other water-soluble vitamins when in-
cluded in the diet at levels much higher than the nutri-
tional requirement. A main reason for its toxicity is that
pyridoxine's passive absorption allows the uptake of
massive doses, unlike a saturable absorption mecha-
nism such as that of riboflavin. Consequently, pyridox-
ine has an acute oral I~D50 value greater than that of
riboflavin.
Once ingested, Pyridoxine must be converted to its
active forms, PEP and PMP. The conversion requires
flavomononucleotides (FMN), Ravine adenine dinucleo-
tide (FAD), and niacinamide adenine dinucleotide
(NAD). Therefore, a deficiency of niacin or riboflavin
necessary for the formation of NAD and FAD, respec-
tively, can result in decreased levels of the active forms
of pyridoxine. Pyridoxal phosphate functions with
kynureninase in the synthesis of niacin from trypto-
phan. In Pyridoxine deficiency, the diminution of this
reaction results in the, formation of xanthurenic acid,
which is excreted in the urine. Urinary xanthurenic acid
is therefore a sensitive indicator of Pyridoxine defi-
ciency. About 70 percent of the vitamin is excreted in
the urine as the inactive metabolite 4-pyridoxic acid.
HYPERVITAMINOSIS
The toxicity of Pyridoxine has been studied in several
investigations (Table 14~. Adams et al. (1967) fed diets
containing 4.8 or 9.2 mg of PN (PN HC1) to 7-kg early
weaned pigs for 122 days and reported better growth
and feed efficiency with the higher level of supplemen-
tation. Dogs given oral doses of 20 mg/kg of BW for 75
days did not develop any toxic signs (Unna and Antopol,
1940~. Phillips et al. (1978) administered higher oral
doses of 50 mg of PN HCl/kg of BW/day and reported
no signs of toxicity.
Higher doses of the vitamin have been found to pro-
duce signs of toxicity. Phillips et al. (1978) reported that
ataxia, muscle weakness, and loss of balance developed
between 40 and 75 days in dogs that received 200 mg of
PN HCl/kg of BW/day. Dogs fed daily doses of 250 ma/
kg/day began to develop incoordination and ataxia
within the first week of treatment. The dose was then
reduced to 200 mg/kg of BW/day for the remainder of
the experimental period. Histological examination of
the tissues revealed bilateral loss of myelin and axons in
the dorsal funiculi and loss of myelin in individual fibers
of the dorsal nerve roots. A lesser amount of pathologi-
cal damage was observed in dogs receiving 50 mg/kg of
BW/day. Analyses of tissues revealed elevated concen-
trations of PN in the blood, cerebral cortex, spinal cord,
spleen, kidney, and muscle of animals receiving 200 ma/
kg/day. The group receiving 50 mg/kg of BW/day had
elevated PN levels only in the blood and cerebral cortex.
Schaeppi and Krinke (1982) and Antopol and Tarlov
(1942) administered oral doses of 1.5 or 3 g of PN HCl/
kg of BW/day to (logs weighing about 10 kg for periods
of up to 26 days. Toxicity was noted after 2 days. Histo-
logical lesions of the sensory neurons and spinal column
were recorded.
Hoover and Carlton (1981) administered daily doses
of PN HCl to beagle dogs according to a regimen that
raised the dose from 50 to 150 mg/kg of BW by the
fifteenth day and continued at that level for 85 days. The
Pyridoxine treatment produced anorexia within 2
weeks and ataxia within 4 weeks. Krinke et al. (1980)
administered daily oral doses of 300 mg of PN HCl/kg
of BW to pairs of 7- to 11-month-old beagle dogs for 78
days. They reported the development of a locomotory
abnormality (swaying gait) within 9 days. Treated dogs
eventually be-came unable to walk, but did not show
muscular weakness. It was concluded that Pyridoxine
produced a toxic, peripheral, sensory neuronopathy in-
volving degeneration of the dorsal root ganglia, gasse-
rian ganglia, and sensory nerve fibers.
Workers have fed diets containing up to 1,430 mg of
PN HCl per kg to growing and breeding rats over pro-
longed periods with no adverse effects (Brie and Thiele,
1967; Cohen et al., 1973; Stowe et al., 1974; Alton-
Mackey and Walker, 1978; Kirksey and Susten, 1978;
Sloger and Reynolds, 1980; Mercer et al., 1984~. In addi-
tion, daily oral doses of up to 2.5 mg of PN · HCl/rat over
a prolonged period, or oral doses of 9 mg of PN HCl
given on each of 2 successive days did not result in any
adverse effects (Unna and Antopol, 19401.
When Erabi et al. (1983) injected PLP into the ventric-
ular sinus of rats, the animals exhibited convulsions.
Weigand et al. (1940) administered single intravenous
doses of 300 to 700 mg of PN ~ HCl/kg of BW to mice or
rats. They reported mortality in mice with doses higher
than 300 mg/kg and in rats with doses higher than 500
mg/kg. The acute LD50 value for mice was estimated to
be 545.3 mg/kg. For rats it was 657.5 mg/kg. Schu-
macher et al. (1965) fed diets containing 2.5 (control) or
OCR for page 60
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OCR for page 62
62 Vitamin Tolerance of Animals
62.5 mg of PN/kg ad libitum to female rats from 2 weeks
before mating through gestation and lactation. They
reported that the reproduction of the high-PN group
was reduced by 47 percent versus 68 percent in the
control group. Other investigations have not confirmed
this result. Mean birth weight, mean number of pups
per litter, and mean pup weight at weaning were not
affected significantly. The higher level of dietary PN
resulted in a significant increase of 0.79 to 1.23 fig in the
carcass PN content of the newborns. The level did not
affect the PN requirement of the weanling animals.
Krinke et al. (1978) administered an oral dose of 300 mg
of PN HCl/kg of BW to male rats for 31 days. They
observed a slight ataxia. A single intraperitoneal dose of
1,000 mg/kg of BW administered to dams the twenty-
first day of gestation had no adverse effects on repro-
duction (Susten and Kirksey, 19701. There were
apparent stimulations of tyrosine transaminase and hol-
otyrosine transaminase activities in both dams arid fe-
tuses. Single oral or subcutaneous doses of up to 7 g/kg
of BW were administered in the investigations of Anto-
pol and Tarlov (1942) and Unna and Antopol (1940~.
After 24 hours, workers noted uncoordinated move-
ment and tonic convulsions. They observed rarefaction
of the posterior columns of the spinal cord. The LD50
values for PN HCl in rats were determined to be 6 g/kg
of BW by the oral route and 3.7 g/kg of BW by the
subcutaneous route. The corresponding values for PN
were 4 and 3.1 g/kg of BW. The 19 percent difference in
the acute toxicity by the subcutaneous route between
these two forms of the vitamin is consistent with the 18
percent difference in their molecular weights. This sug-
gests that the toxicity is attributable to the pyridoxine
portion rather than to the hydrochloride component.
Unna (1940) administered subcutaneous and oral
doses of 1 to 8 g of PN or PN HCl to 120- to 150-g rats
and reported that up to 1 g/kg of BW was tolerated
without adverse effects. Larger doses resulted in mus-
cular incoordination in 2 or 3 days leading to convulsions
and death. By subcutaneous administration, the LD50
values were 3.1 g/kg of BW for PN and 3.7 a/k~ of BW
for PN HC1. By oral administration, the LD50 of
PN HCl was 5.5 g/kg of BW, which suggested that the
vitamin in that form was readily absorbed from the gas-
trointestinal tract. In addition, young 30-g rats given
daily oral doses of 0.5 to 2.5 mg of PN for 80 days
showed no adverse growth effects.
Pyridoxine has been used at high doses in humans as a
treatment for conditions ranging *om premenstrual
syndrome to schizophrenia. Oral doses of 2 to 6 g/day to
adults over a prolonged period are associated with
sensory-nervous system dysfunction and disablement
(Schaumburg et al., 1983~. Pyridoxine has also been
used to depress abnormally high lactation in women
(Rose, 1978), possibly by increasing the formation of
dopamine. Prolactin was decreased by doses of 200 mg
of PN given 3 times a day (Rose, 1978~.
PRESUMED UPPER SAFE LEVELS
Insufficient data are available to support estimates of
the maximum dietary tolerable levels of vitamin Be for
species other than the dog and the laboratory rat. Levels
of PN of 1,000 mg/kg of diet fed for less than 60 days, or
less than 500 mg/kg of diet fed for more than 60 days,
appear to be safe for dogs.
The available data suggest that rats may safely be fed
diets containing up to 500 mg of PN/kg for less than 60
days, or up to 250 mg of PN/kg for more than 60 days.
Estimates of the dietary levels of PN HCl that produce
specific tissue and body fluid saturation in rats following
exposure for more than 60 days are: muscle, 2.4 mg/kg;
liver, 4.8 mg/kg; milk, 9.6 mg/kg. Estimates of the acute
oral LD50 for the rat are 3.1 to 4 g/kg for PN and 3.7 to 6
g/kg for PN HC1. It is suggested that dietary levels of at
least 50 times nutritional requirements are safe for most
species.
SUMMARY
1. Vitamin Be (pyridoxine) is a water-soluble vitamin
that is absorbed readily. Some domestic and laboratory
animals require a dietary source of the vitamin.
2. Pyridoxine can be toxic to animals when adminis-
tered athighlevels. Alevel of 1,000 mgof PN HCl/kgof
diet appears safe for dogs. Rats may safely be fed
diets containing up to 500 mg of PN/kg for less than 60
days, or up to 250 mg of PN/kg for more than 60 days.
Estimates of the dietary levels of PN HCl that produce
specific tissue and body fluid saturation in rats following
exposure for more than 60 days are: muscle, 2.4 mg/kg;
liver, 4.8 mg/kg; milk, 9.6 mg/kg. Estimates of the acute
oral LD50 for the rat are 3.1 to 4 g/kg for PN and 3.7 to 6
g/kg for PN HC1.
3. Available evidence from dog and rat studies sug-
gests that probably more than 1,000 times the nutri-
tional requirements would have to be included in diets in
order to produce signs of toxicity in these particular
species.
REFERENCES
Adams, C. R., C. E. Richardson, and T. J. Cunha. 1967. Supplemental
biotin and vitamin Be for swine. J. Anim. Sci. 26:903. (Abstr.)
AlLon-Mackey, M. G., and B. L,. Walker. 1978. The physical and neu
romotor development of progeny of female rats fed graded levels of
pyridoxine during lactation. Am. J. Clin. Nutr. 31:76.
OCR for page 63
Vitamin B6 (Pyridoxine) 63
Antopol, W., and I. M. Tarlov.1942. Experimental study of the effects
produced by large doses of vitamin B6. J. Neuropathol. Exp. Neurol.
1:330.
Brin, M., and V. F. Thiele. 1967. Relationships between vitamin B6
vitamer content and the activities of two transaminase enzymes in
rat tissues at varying intake levels of vitamin B6. J. Nutr. 93:213.
Cohen, P. A., K. Shneidman, F. Ginsberg-Fellner, J. A. Sturman,
J. Knittle, and G. E. Gaull. 1973. High pyridoxine diet in the rat:
Possible implications for mecavitamin therapy. J. Nutr. 103:143.
Cox, S. H., A. Murray, and I. V. Boone. 1962. Metabolism of tritium-
labelled pyridoxine in rats. Proc. Soc. Exp. Biol. Med. 109:242.
Erabi, M., D. E. Metzler, and W. R. Christensen. 1983. Convulsant
activity of pyridoxal sulphate and phosphoethyl pyridoxal: Antago-
nism by GABA and its synthetic analogues. Neuropharmacology
22:865.
Hoover, D. M., and W. W. Carlton. 1981. The subacute neurotoxicity
of excess pyridoxine HCl and clioquinol (5-chloro-7-iodo-8-hydroxy-
quinoline) in beagle dogs. 1. Clinical disease. Vet. Pathol. 18:745.
Khera, K. S. 1975. Teratogenicity study in rats given high doses of
pyridoxine (vitamin B6) during organogenesis. Experientia 31:469.
Kirksey, A., and S. S. Susten. 1978. Influence of different levels of
dietary pyridoxine on milk composition in the rat. J. Nutr.108:113.
Krinke, G., J. Heid, H. Bittiger, and R. Hess.1978. Sensory denerva-
tion of the planter lumbrical muscle spindles in pyridoxine neuropa-
thy. Acta Neuropathol. 43:213.
Krinke, G., H. H. Schaumberg, P. S. Spencer, J. Suter, P. Thomann,
and R. Hess.1980. Pyridoxine megavitaminosis produces degener-
ation of peripheral sensory neurons (sensory neuronopathy) in the
dog. Neurotoxicology 2:13.
Mercer, L. P., J. M. Gustafson, P. T. Higbee, C. E. Geno, M. R.
Schweisthal, and T. B. Cole.1984. Control of physiological response
in the rat by dietary nutrient concentration. J. Nutr. 114:144.
National Research Council. 1978. Nutrient Requirements of Labora-
tory Animals, 3rd rev. ed. Washington, D.C.: National Academy
Press.
Phillips, W. E. J., J. H. L. Mills, S. M. Charbonneau, L. Tryphonas,
G. V. Hatina, Z. Zawidzka, F. R. Bryce, and I. C. Munro. 1978.
Subacute toxicity of pyridoxine hydrochloride in the beagle dog.
Toxicol. Appl. Pharmacol. 44:323.
Rose, D. 1978. Interactions between vitamin Bfi and hormones. Vit.
Horm. 36:53.
Schaeppi, U., and G. Krinke. 1982. Pyridoxine neuropathy: Correla-
tion of functional tests and neuropathology in beagle dogs treated
with large doses of B6. Agents Actions 12:575.
Schaumburg, H., J. Kaplan, A. Windebank, N. Vick, S. Rasmus,
D. Pleasure, and M. J. Brown.1983. Sensory neuropathy from pyri-
doxine abuse: A new megavitamin syndrome. N. Engl. J. Med.
309:445.
Schumacher, M. F., M. A. Williams, and R. L. Lyman.1965. Effect of
high intakes of thiamine, riboflavin and pyridoxine on reproduction
in rats and vitamin requirements of the offspring. J. Nutr. 86:343.
Scudi, J. V., K. Unna, and W. Antopol. 1940. A study of the urinary
excretion of vitamin B6 by a colorimetric method. J. Biol. Chem.
135:371.
Sloger, M. S., and R. D. Reynolds. 1980. Effects of pregnancy and
lactation on pyridoxal 5'-phosphate in plasma, blood and liver of rats
fed three levels of vitamin B6. J. Nutr. 110:1517.
Stowe, H. D., R. A. Croyer, P. Medley, and M. Cates.1974. Influence
of dietary pyridoxine in cadmium toxicity in rats. Arch. Environ.
Health 28:209.
Susten, S. S., and A. Kirksey. 1970. Influence of pyridoxine on tyro-
sine transaminase activity in maternal and fetal rat liver. J. Nutr.
100:369.
Unna, K.1940. Studies on the toxicity and pharmacology of vitamin B6
(2-methyl-3-hydroxy-4,5-bis(hydroxymethyl)-pyridoxine).
J. Pharmacol. 70:400.
Unna, K., and W. Antopol. 1940. Toxicity of vitamin B6. Proc. Soc.
Exp. Biol. Med. 43:116.
Weigand, C. G., C. R. Eckler, and K. K. Chan. 1940. Action and
toxicity of vitamin B6 hydrochloride. Proc. Soc. Exp. Biol. Med.
44:147.
Representative terms from entire chapter:
fed diets
