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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

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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

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60 ~4 Pi 4= To ~ C: .o E ~ W C o E by .= be ; so cn 1:: = ~ .~ ~o ~ o ~ cn Z. Cal Cal Cal o ~Cal o ~o o ~oo ~ 3 i w ~ ~ i t w ~ L C a a ~ , v i ~ ~ ~ ~ At, ~ g ~ ~w 3 o ~ z ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ o m ~ ~ ~ ~ To ~ ~ ~ ~ ~ ~ ~ A ~ ~ o ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~>> ~. ~ O O O O O O O O O ~ O O cn O O O a ~ u ~cn co u~ 0 ~o ~ Oo ~3 ~=, bo ~_ _ _ _ _ ~00 _ co cn _ cn CQ ~? oo c~ z D D z ~CC 5 ' ~O ~- Z Z Z Z Z Z Z Z ZZZ ZZ Z Z Z :L ~P ~P" ~ O. bC Ln ~ ~ ~ O y y 3 ca w y y ca e ~ e ~ R ~ O O o ~0 g bc L ~I o ba ~3 C ~If) U ~C ~C ~CO CO _ C ~_ ~_ ~C ~C ~O oo 0 oo ~_ ~ ~X bC ~E b ~E bO ~E y ~ ~, O ~y ~ ~ bO ~_ ~ ~_ c ~ _ ~ 00 ~ _ ~ CL C`)^ ~=, 30 t'D^ ~0 ~C~ ~D ~E ilJ ~ D ~D ~ E ~' ~ D ~E ~ ~E E L ~o E b4 5,o ~t)4 ~ O o o ~o ~ ~ o ~o ~ o ~ ~ o ~o ~ ~- ct ~(t C\ ~C ~C\S . a a a a a a a a x ~ ~

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61 ~a to to (s) ~- cr) - ~c c ~' ( ~ ^ ~- .- .< s ~X ~ ~ a `~, y a w c c c ~ ~ ~ ~ us ~ E ~ ~ By ~ ~ ~ w ~ E 3 0 y Y a ~ Y ~y ~a S ~ , ~ Y Y E Y , e ~ in 3 ~ ~ e ~j ~ c ~ _ ~ Ct ~ ~ ~- ~ ~ ~Cal ~- oa a a a a a a 0 oo ~0 a ~ _ ~O y ~ c E ~ ~E ~ ~n E ~ _ _ e ~c ~u ~CQ CO c~ C ~_ _ _ _ =: t: :t ~:r: =: ~:= ~::n ~ ~ ~ ts zz z z z z z z z zzz z z z z z ~ ~p" p" ~ p~ ~ ~ 4 . . - ~. _ , - b.0 3 ~ E ~, ~E '( ~D ~ y _ E ~,~n c ~0 Lr) _ c ~0 c~ _ ~_ _ _ ~ ~o ba ~o o .= _ ~ ~ ~0 ~ ~0 ~ ~ ~ _ ~co ~_ ~ _ ~ _ u ~cD ~ { ~- ~:^ z ,,, = ~ a a ~B ~ a ~e ~ a ~& 00 ~ ~ ~ ~ ~ ~ ~ ~ 3 ~ 0 ,, ~ <; <,, & ~ ~ ~ ~j; _ O O ~ c~ - ~c,:, ~ ~ , ~ ~ ~ ~ ~ ~ ~ '> ' ~ ~ ~ ~ c~ ~ ~ _ ~5 ~ (Q ~ ~t ~ < ~ ~ ct ~ ~ ~ ~ (/) ~3 c ~P: ~ ~: ~cn

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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.

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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.