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B ~ 1otln Biotin is distributed widely in low concentrations in plant and animal tissues. It was first described as the factor protecting against egg white injury caused by avidin, a glycoprotein that binds biotin in the intestinal tract and thus inhibits biotin absorption. Biotin is slightly soluble in water. This vitamin has a bicyclic structure consisting of a ureido ring fused with a tetra- hydrothiophine ring bearing a Valerie acid side chain (Figure 16~. NUTRITIONAL ROLE Dietary Requirements of Various Species Although animals have a metabolic requirement for biotin, it is not yet established that it is a dietary essen- tial for all species, due to widespread intestinal synthe- sis. The administration of certain sulfa drugs can be used to induce biotin deficiencies. Dietary requirements have been established for poultry, but not for most other animals. The broiler chick needs 0.15 mg of biotin/kg of diet and the turkey poult, 0.2 mg/kg (National Research Council, 1984~. Eight stereoisomers of the biotin molecule are possi- ble but only one, D-biotin (cis), is physiologically active. Much of the biotin in natural materials is present in the bound form, of c-N-biotinyl-~-lysine in proteins. The bio- log;ical availability of this form, which is called biocytin, depends upon the digestibility of the proteins in which it is found. The supplementary form generally used for animal feeds is synthetic D-biotin. Biochemical Functions Biotin is known to take part in metabolic carboxyla- tion reactions (Bonjour, 1984~. Most biotin-dependent reactions in mammals are energy-dependent. The reac- tion involves the cleavage of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate. Most biotin-dependent reactions in mamma- lian tissues appear to be of this type. The exception is a transcarboxylation that is not energy-dependent. The biotin-catalyzed carboxylase systems consist of three types of subunits: biotin carboxylase, carboxyl trans- ferase, and carboxyl carrier protein. Biotin is covalently linked to the carboxyl carrier protein through a peptide bond to the e-amino group of lysine (that is, as biocytin). The most important of the biotin-dependent carboxyla- tion enzymes are pyruvate carboxylase, acetyl CoA car- boxylase, and propionyl CoA carboxylase. ABSORPTION AND METABOLISM Biotin appears to be absorbed well from the small intestine (Marks, 1979), although the protein-bound forms in feeds are not readily available to animals. Present evidence suggests that the vitamin is not re- tained well. A high proportion of administered biotin has been recovered intact in the urine of rats and hu- mans following pare nteral ad mins trati on (Fraenkel- Conrat and Fraenkel-Conrat, 1952; Wright et al., 19561. Biotin excretion, like that of most water-soluble vita- mins, is closely related to intake. Biotin acts with a number of carboxylases, which results in the movement of carbon atoms between cellu- lar compartments (Murthy and Mistry, 19771. The biotin-dependent enzyme pyruvate carboxylase con- verts pyruvate to oxaloacetic acid. This reaction is im- portant in gluconeogenesis, the formation of glycerol, and the synthesis of acetylcholine. Two other biotin en- zymes, propionyl-CoA carboxylase and acetyl-CoA car- boxylase, are involved in the synthesis of succinyl CoA. 70

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Biotin 7 1 o 11 , C \ I HC CH I \ H2C S' Biotin ,CH-(CH234 COOH FIGURE 16 Chemical structure of biotin. The former is of major importance in energy utilization in ruminants. Biotin is also required in the fixation of 6-carbon in purines. Thus, it is important in RNA and DNA syntheses. HYPERVITAMINOSIS The effects of the administration of high levels of bio- tin are summarized in Table 15. Very limited data are available. Comben (1979) reported the results of supplementing the diet of breeding sows with 2 mg of biotin/kg of diet for a period of 4 months. He noted reduction in lameness within 5 to 6 weeks, as well as an improvement in repro- duction. No adverse effects were recorded. Bryant et al. (1985a,b,c) conducted a series of trials in which female swine were fed supplemental biotin at levels up to 0.44 mg/kg of diet. Growing animals given a supplementary level of 0.22 mg of biotin/kg of diet showed improved foot health. Growth was unaffected. No adverse effects were noted. During the subsequent breeding period, which extended over four reproduc- tive cycles, the sows were fed either no supplemental biotin or 0.44 mg/kg of diet. Improved foot health, hair coat, and reproduction were noted. No adverse effects were recorded. Adams et al. (1967) fed a diet based on corn, mile, and soybean meal, which contained 0.29 or 0.4 mg of biotin/ kg, to early-weaned pigs. The researchers reported im- proved growth and feed efficiency over a 122-day growth period. No adverse effects of the higher level of biotin were recorded. Brooks et al. (1977) increased the biotin level of breeding sows from 0.15 mg/kg of diet to 0.35 or 0.4 mg/kg. They observed a 28 percent reduc- tion in the incidence of foot lesions. Litter productivity was also increased. No adverse effects of the higher biotin levels were observed. Arends et al. (1971) fed 0.15, 0.25, or 0.33 mg of biotin/kg of diet to 32-week-old breeding turkey hens for 12 or 14 weeks. No significant effects on egg produc- tion or hatchability were noted. However, the egg biotin content was raised from 0.13 mg/kg of egg weight with the control diet to 0.25 mg/kg with the diet containing 0.33 mg of biotin/kg. The mortality of poults from hens fed the biotin-supplemented diets was reduced. The progeny were fed up to 0.37 mg of biotin/kg of diet until they were 4 weeks old. Liver biotin concentration in- creased linearly with the dietary biotin level. Poults fed the highest level of biotin had hepatic biotin concentra- tions of 0.91,ug/g. Brewer and Edwards (1972) fed diets containing 0.02, 0.04, 0.06, 0.1, 0.18, or 0.34 mg of biotin/kg of diet to breeding broiler hens for a 10-week period. Egg produc- tion and fertility were improved with diets containing up to 0.1 mg of biotin/kg. Egg biotin concentration in- creased linearly with increasing levels of the vitamin in the diet. A biotin level of 0.1 mg/kg of diet produced 0.2 ,ug/g of yolk weight; a biotin level of 0.34 mg/kg of diet produced 0.6 Agog of yolk weight. No adverse effects of the higher biotin levels were noted. Whitehead and Randall (1982) added 0.04 to 0.5 mg of biotin/kg to the diets of growing broiler chickens from 1 day to 8 weeks of age. They reported no adverse ef- fects on mortality. Paul et al. (1973a,b) administered to unmated 3- to 4- month-old female rats 50 mg of biotin/kg of BW in two subcutaneous injections of biotin dissolved in 0.5 ml of 0.1 N sodium hydroxide (NaOH). The rats were bred 7, 14, or 21 days after treatment. They were sacrificed 15 or 22 days after gestation. The biotin-treated rats showed irregular estrous cycles. Atrophic changes were observed in the corpora lutea. A large number of the treated animals resorbed their fetuses by the twenty-second day of gestation, even when mated within 7 days following treatment. Fetal and placental weights were also reduced. Paul and Duttagupta (1975) administered a subcuta- neous dose of 100 mg of biotin/100 g of BW to female rats on the first and second days of gestation. They reported resorption of fetuses and placentas in 7 of the 8 treated animals by 21 days of gestation. In a subsequent investigation, Paul and Duttagupta (1976) administered a subcutaneous dose of D-biotin in 0.1 NNaOH to female rats on the fourteenth and fifteenth days of gestation. Resorption of fetuses and placentas occurred in 2 out of 11 animals. Maternal, uterine, fetal, and placental weights were reduced in the others. Mittelholzer (1976) was unable to reproduce those ef- fects using a similar protocol. In this study, pure D-biotin was administered to 190- to 240-g female rats that were known to be cycling. On the day of vaginal estrus, each rat, with the exception of those in the control group, was given subcutaneous injections totalling 5 or 50 mg of

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72 E E W ~C =~ - .= ~ of C hobo ~ } US - 1 ~ E - In C: ~ oo 3 ~ 4 - o ~ E ~ E a a w U) ~ 0 ~ be Go O b4 ~0 _ b,O ~ O p. a~ >, ~ ~ ~ .~ ~ ~L' ~ ~ O - O a, ~ ~} q) ~b4 0 t4-- Z ~Z 4= ~ ._ ._ ._ 3 - o C~ - ~: 3 3 o oo _ _ ._ ~o ho tn co ^ o C ~C~J o o o ~: ._._ oo ._._ ~_ ~4 o U~ - o C~ U' ~ U) =5 c: _ m ~ O ~C~ C ~_ u, cn ~ U) ~n ~ - ~ ~ - .! ~ ~ - - cs) ~ - - u) -53 ~^ rQ .5 ~ o ~ ~ - .> o .~ ~ 3 ~ ~ b~ ~: 4= ~ . _ C~0 ~ .s CD ~ .~4 ~C ~ ~ ,.~: o ._ ~ z a) ~ ._ ._._ ~o 3 ~ ._ 4= o ._ ._ ~, b4 ~4 o 1 o o ~ 3 ns o~ r~ - ~oo =. ~ _ _ _ _ cn ~ ~: o o s~ ~soo =.5) ~_ ~ ~=. __ _ cn~ ~ ~_ ~ D ~ ~ ~ F o ~ = ~ ~ ~: ~h_ ~ . . . . ~o ~ ~ o - ~ ~ CD t\, ~-o, ,o, ~ O _ - ) = h g ~I e =~ .~ ~ .~ ~ ~ ~ _ c: ~ c o 31 3 ~ ~ o , c C~: Pt U: - o ~L {: ~ ._._._._._ ooooo ~ ,=,=,= ~o o bbbbb ~a:> ._ b~ b4 ~ o 'C~o 4= :^ .~ t,,o C~ ~ o ~_ Co~ ~ ; ~ tn ~,- 5 07 3 3 3 3 _^ ~ ~ 3 ~3 ~=^ =^ ~3 3 3 ~n cn cn ~b~ ~4= ::5 =; ~ t_ _ Cr) - 53 _ ~ _ rc5 C) CC ~, c~ ~ S ~ o ~ ~ . _ o ~C U] - ~: C~ ~Q C'0 ~ 3 o - 3 ~ c,, _. _ 4 - ._ ta~ ~o~ .. oo ~ c: ~ ~o Em b4 = C~ Co C~ _ o o ~ _ ~ CD~y o oo 4= C ~CO C~0 C,0CO ' ~V ~V 3 E ~sE ~ . ~_ 3 3 ~ ~4 y b4 o U~ ~o cn o 2 o t:: . o . a ~o ~o o o - o ._ 4= co cn 0 ~ ~ ~ d, - - - o z - o - ~: ._ 4 - o ._ a ._ _ co _ u' ~ ~, t4 30 - ._ o ._ a b40 8o _Lr) b4 o s~ U~o CO_ _4C~ _ u'~nco ___ ~Ct CCCCU) 4=4=4= CtC~ CS) 5) - au o - 4 - . ~4 .= ~2 .= o . 4 - ~: cn `: .= U' o z

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Biotin 73 biotin/kg of BW with 0.1 NNaOH as the carrier vehicle. Treatment consisted of two doses spaced 6 hours apart. It was found that 88 percent of rats receiving 5 mg/kg carried fetuses at 21 days of gestation. This rate was 71 percent in the high-biotin group and 67 percent in the control group. No significant differences were noted in implantation rate, number of resorption sites, fetal weight, placental weight, or ovarian weight. PRESUMED UPPER SAFE LEVELS Insufficient data are available to support estimates of the maximum dietary tolerable levels of biotin. Results from one laboratory suggest that biotin may be toxic to fetal rats when it is administered subcutaneously to the dam. This effect, however, was not reproduced by an- other researcher who followed a similar protocol. Stud- ies with poultry and swine indicate that these species can safely tolerate dietary levels of at least 4 times their nutritional requirements of biotin. In view of the poor retention of biotin, it is probable that these species can tolerate much higher levels. SUMMARY 1. Biotin is a water-soluble vitamin that many species of animals require in the diet. For other species, gut microbial synthesis provides sufficient biotin. The vita- min appears to be well absorbed from the gut, but is not well retained. 2. Studies with poultry and swine indicate that these species can safely tolerate dietary levels of 4 to 10 times their nutritional requirements of biotin. Because this vitamin is not well retained, the maximum tolerable level of biotin may be much higher. 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.) Arends, L. G., E. W. Kienholz, J. V. Schutze, and D. D. Taylor. 1971. Effect of supplemental biotin on reproductive performance of tur- key breeder hens and its effect on the subsequent progeny's perfor- mance. Poult. Sci. 50:208. Bonjour, J. P. 1984. Biotin. P. 403 in Handbook of Vitamins, L. J. Machlin, ed. New York: Marcel Dekker. Brewer, L. E., and H. M. Edwards, Jr. 1972. Studies on the biotin requirement of broiler breeders. Poult. Sci. 51:619. Brooks, P. H., D. A. Smith, and V. C. R. Irwin. 1977. Biotin-Supple- mentation of diets, the incidence of foot lesions, and the reproduc- tive performance of sows. Vet. Rec. 101:46. Bryant, K. L., E. T. Kornegay, J. W. Knight, K. E. Webb, Jr., and D. R. Notter. 1985a. Supplemental biotin for swine. II. Influence of sup- plementation to corn-and-wheat-based diets on reproductive perfor- mance and various biochemical criteria of sows during four parities. J. Anim. Sci. 60:145. Bryant, K. L., E. T. Kornegay, J. W. Knight, H. P. Veit, and D. R. Notter.1985b. Supplemental biotin for swine. III. Influence of sup- plementation to corn-and-wheat based diets on the incidence and severity of toe lesions, hair and skin characteristics and structural soundness of sows housed in confinement during four parities. J. Anim. Sci. 60:154. Bryant, K. L., E. T. Kornegay, J. W. Knight, K. E. Webb, Jr., and D. R. Notter.1985c. Supplemental biotin for swine. I. Influence on feedlot performance, plasma biotin and toe lesions in developing gilts. J. Anim. Sci. 60:136. Comben, N. 1979. Biotin for Breeding Sows. Field Experiences 1976-1978. Publication #1979-270-79-955. Basel, Switzerland: F. Hoffman-LaRoche. Fraenkel-Conrat, J., and H. Fraenkel-Conrat.1952. Metabolic fate of biotin and of avidin-biotin complex upon parenteral administration. Biochem. Biophys. Acta 8:66. Marks, J. 1979. A Guide to Vitamins. Lancaster, England: Medical and Technical Publishing. Mittelholzer, E.1976. Absence of influence of high doses of biotin on reproductive performance in female rats. Int. J. Vit. Res. 46:33. Murthy, P. N. A., and S. P. Mistry.1977. Biotin. Prog. Food Nutr. Sci. 2:405. National Research Council. 1984. Nutrient Requirements of Poultry. 8th rev. ed. Washington, D.C.: National Academy Press. Paul, P. K., and P. N. Duttagupta.1975. The effect of an acute dose of biotin at the pre-implantation stage and its relation with female sex steroids in the rat. J. Nutr. Sci. Vitaminol.21:89. Paul, P. K., and P. N. Duttagupta.1976. The effect of an acute dose of biotin at the post-implantation stage and its relation with the female sex steroids in the rat. J. Nutr. Sci. Vitaminol. 22:181. Paul, F'. K., P. N. Duttagupta, and H. C. Agarwal. 1973a. Antifertility effect of biotin and its amelioration by estrogen in the female rat. Curr. Sci. 42:613. Paul, P. K., P. N. Duttagupta, and H. C. Agarwal. 1973b. Effects of an acute dose of biotin on the reproductive organs of the female rat. Curr. Sci. 42:206. Whitehead, C. C., and C. J. Randall. 1982. Interrelationships between biotin, choline and other B-vitamins and the occurrence of fatty liver and kidney syndrome and sudden death syndrome in broiler chick- ens. Br. J. Nutr. 48:177. Wright, L. D., E. L. Cresson, and C. A. Driscoll. 1956. Biotin deriva- tives in human urine. Proc. Soc. Exp. Biol. Med. 91:248.