Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 115
Page 115 8 Water-Soluble Vitamins VITAMIN C Vitamin C (L-ascorbic acid) is a water-soluble antioxidant that can be synthesized by many mammals, but not by humans. In the diet, it is also present to some extent in its oxidized form (dehydroascorbic acid), which also has vitamin C activity (Sabry et al., 1958). Dietary deficiency eventually leads to scurvy, a serious disease characterized by weakening of collagenous structures that results in widespread capillary hemorrhaging (Hornig, 1975; Woodruff, 1975). In the United States, scurvy occurs primarily in infants fed diets consisting exclusively of cow's milk and in aged persons on limited diets. The best defined biochemical property of vitamin C is its function as a cosubstrate in hydroxylations requiring molecular oxygen, as in the hydroxylation of proline and lysine in the formation of collagen (Barnes, 1975; Myllyla et al., 1978), of dopamine to norepinephrine (Levin et al., 1960), and of tryptophan to 5-hydroxytryptophan (Cooper, 1961). It may also be involved in reactions involving a number of other compounds, including tyrosine (La Du and Zannoni, 1961), folic acid (Stokes et al., 1975), histamine (Clemetson, 1980), corticosteroids (Wilbur and Walter, 1977), neuroendocrine peptides (Glembotski, 1987), and bile acids (Ginter, 1975). Vitamin C can also affect functions of leukocytes (Anderson and Theron, 1979) and macrophages (Anderson and Lukey, 1987), immune responses (Leibovitz and Siegel, 1978), wound healing (Levenson et al., 1971), and allergic reactions (Dawson and West, 1965). Ascorbic acid as such or as present in plant foods increases the absorption of inorganic iron when the two nutrients are ingested together (Hallberg et al., 1987).
OCR for page 116
Page 116 Absorption, Transport, Storage, and Excretion L-ascorbic acid is absorbed in the intestine by a sodium-dependent transport process (Stevenson, 1974). At low doses, absorption may be almost complete, but over the range of usual intake in food (30 to 60 mg), 80 to 90% is absorbed (Kallner et al., 1977). Absorbed ascorbic acid is present as the anion in blood plasma, unbound to plasma proteins. As the daily intake of ascorbic acid increases, the plasma concentration rises rapidly and then reaches a plateau of 1.2 to 1.5 mg/dl at an intake of 90 to 150 mg/day (Garry et al., 1987; Sauberlich et al., 1974). Body stores of ascorbic acid in adult men reach a maximum of approximately 3,000 mg at daily intakes exceeding 200 mg. One half' of this level (1,500 mg) is achieved by much lower daily intakes in the range of 60 to 100 mg. Much of the body stores is normally found within cells, in which the concentrations vary widely but are usually severalfold higher than those in blood plasma. In at least some tissues these concentrations appear to be achieved by a stereoselective transport process (Moser, 1987). Ascorbic acid and its various metabolites are excreted mainly in the urine. At daily intakes up to 100 mg, oxalate is the major product excreted. When larger amounts are ingested, ascorbic acid is mainly excreted as such (Jaffe, 1984; Kallner et al., 1979). Little ascorbic acid is metabolized to carbon dioxide at ordinary intakes (Baker et al., 1969), but at large doses, degradation within the intestine may be substantial (Kallner et al., 1985). Dietary Sources and Usual Intakes Vegetables and fruits contain relatively high concentrations of vitamin C, e.g., green and red peppers, collard greens, broccoli, spinach, tomatoes, potatoes, strawberries, and oranges and other citrus fruits. Meat, fish, poultry, eggs, and dairy products contain smaller amounts, and grains contain none. Ascorbic acid in the U.S. food supply is provided almost entirely by foods of vegetable origin-38% by citrus fruits, 16% by potatoes, and 32% from other vegetables (Marsten and Raper, 1987). The rest comes from fortified and enriched products and from meat, fish, poultry, eggs, and dairy products. The average amount available per capita in the U.S. food supply increased from 98 mg in 1967-1969 to 114 mg in 1985 (Marsten and Raper, 1987). The average dietary vitamin C intake by adult men in the United States in 1985 was 109 mg (USDA, 1986). The corresponding intakes for adult women and children 1 to 5 years of age were 77 mg and 84 mg, respectively (USDA, 1987).
OCR for page 117
Page 117 The dietary vitamin C may be considerably lower than the calculated amount in the food ingested, largely because of its destruction by heat and oxygen and its loss in cooking water. On the other hand, the mean total intake of vitamin C may also be considerably higher because (1) supplements of vitamin C are ingested by 35% of a representative U.S. adult population (Stewart et al., 1985), (2) food composition tables used in the U.S. Department of Agriculture surveys provide the L-ascorbic acid content only and do not include the biologically active dehydroascorbate, and (3) ascorbic acid is added to some processed foods because of its antioxidant or other properties (NRC, 1982). Criteria for Assessing Nutritional Status Vitamin C status is usually evaluated from signs of clinical deficiency, plasma (or blood) levels, or leukocyte concentrations. It has also been evaluated from isotopic estimates of body stores. Clinical signs of scurvy, including follicular hyperkeratosis, swollen or bleeding gums, petechial hemorrhages, and joint pain, are associated with plasma (or serum) vitamin C values of less than 0.2 mg/ dl, leukocyte concentrations of less than 2 µg/108 cells, and a body pool size of less than 300 mg (Hodges et al., 1969, 1971; Sauberlich, 1981). To eliminate clinical signs of scurvy in several groups of male subjects, vitamin C intakes ranging from 6.5 to 10 mg/day were required (Baker et al., 1971; Bartley et al., 1953; Hodges et al., 1969, 1971). Recommended Allowances Adults The dietary allowances for vitamin C must be set, somewhat arbitrarily, between the amount necessary to prevent overt symptoms of scurvy (approximately 10 mg/day in adults) and the amount beyond which the bulk of vitamin C is not retained in the body, but rather is excreted as such in the urine (approximately 200 mg/day). Between these limits, body stores vary directly with intake, albeit not linearly. Since vitamin C is poorly retained in the body in the absence of continuous intake, the RDA has traditionally been set at a level that will prevent scorbutic symptoms for several weeks on a diet lacking vitamin C. Observed depletion rates in a small group of well-nourished adult men with a body pool of approximately 1,500 mg were exponential and averaged 3.2% daily (range, 2.2 to 4.1% in nine subjects), which would yield a body pool of vitamin C of 300 mg (the amount below which scorbutic symptoms can occur) in about
OCR for page 118
Page 118 30 days (Baker et al., 197 1). In 6 of 11 healthy, well-nourished young women fed ascorbate-free diets, scorbutic symptoms developed within 24 days (bleeding, red, or tender gums) in association with blood levels consistent with body stores below 300 mg (Sauberlich et al., in press). By means of steady state analysis of ascorbate kinetics in men, Kallner et al. (1979) found the turnover time to vary from about 56 days at low intakes (approximately 15 mg/day) to about 14 days at intakes of approximately 80 mg/day. Above 80 mg/day, urinary excretion of unmetabolized ascorbate increased rapidly. Kallner and colleagues reported that a three-pool model was required to fit the observed kinetic data and postulated that one of these pools reflected ascorbate bound within cells. They also failed to observe a clear-cut renal threshold for ascorbate. Since the turnover time varied with tissue stores, Kallner (1987) proposed that the depletion rates observed in earlier studies might be erroneously low. Saturation of tissue binding, and maximal rates of metabolism and renal tubular absorption, seemed to be approached at turnover rates of 60 to 80 mg daily, equivalent to body stores of about 1,500 mg. The subcommittee has set the RDA for adult men at 60 mg/day, the same as in the previous edition. This amount is based upon (1) the observed variation in depletion rates and turnover rates; (2) the average depletion rates and the steady state turnover rates at a pool size of 1,500 mg; (3) the less than complete absorption of ascorbic acid, estimated at 85% for usual intakes; and (4) the variable loss of ascorbic acid in food preparation. This level of intake will prevent signs of scurvy for at least 4 weeks. Given the development of early scorbutic symptoms in adult women considered to be well nourished after somewhat less than 4 weeks of depletion, the subcommittee recommends the same RDA for adult women as for men. An intake of 60 mg is easily provided in ordinary mixed diets. In the previous edition of the RDAs, an intake of 45 mg/day for adult men was considered to provide an average pool size of 1,500 mg, and an intake of 60 mg/day was recommended to provide a margin of safety. Higher values, in fact, have been suggested to yield a pool size of 1,500 mg (Kallner, 1987), which would result in a recommended allowance of about 100 mg/day. It was the view of the subcommittee, however, that an allowance of 60 mg/day for both men and women provides an adequate margin of safety. Persons 65 years and older ingest more vitamin C on the average (90 to 150 mg/day) than the mean intake for all ages (Garry et al., 1982; USDA, 1984). Low plasma concentrations are, however, observed frequently in some groups of elderly persons (Cheng et al., 1985; Newton et al., 1985). Such low levels are believed to reflect
OCR for page 119
Page 119 inadequate intake in the groups examined. Therefore, no increment in the RDA for the elderly is recommended. Cigarette smokers have lower concentrations of ascorbic acid in serum (Johnson et al., 1984; Pelletier, 1975; Schectman et al., 1989; Smith and Hodges, 1987) and leukocytes (Brook and Grimshaw, 1968). The lower serum levels are only partially explained by the reduced vitamin C intakes of smokers (Schectman et al., 1989). The metabolic turnover of men who smoked 20 or more cigarettes daily was found to be increased to a level 40% greater than that of nonsmoking men (Kallner et al., 1981). From calculations based on all these observations, the vitamin C requirement of smokers has been estimated to be as much as twice that of nonsmokers. The subcommittee recommends that regular cigarette smokers ingest at least 100 mg of vitamin C daily. Pregnancy and Lactation During pregnancy, the concentration of vitamin C and several other solutes in blood plasma decreases (Morse et al., 1975), probably as a result of the hemodilution that accompanies pregnancy (Hytten, 1980; Rivers and Devine, 1975). Fetal and infant plasma levels of vitamin C are 50% higher than those of the mother (Khattab et al., 1970; Salmenpera, 1984), however, indicative both of active transport across the placenta and of a higher relative pool size in the fetus and infant. If the requirement for vitamin C per unit body weight is comparable to that of nonpregnant adults, the increment in requirement for the fetus near term would be small (approximately 3 to 4 mg/ day). Requirements are likely to be somewhat higher because the catabolic rate in the fetus is probably greater. To offset losses from the mother's body pool during pregnancy, a 10 mg/day increment in the maternal vitamin C RDA is recommended during pregnancy. The concentration of vitamin C in human milk varies widely (3 to 10 mg/dl), depending upon the dietary intake of the nutrient as well as other factors (Bates et al., 1983; Byerley and Kirksey, 1985; Salmenpera, 1984; Sneed et al., 1981; Tarjan et al., 1965). Assuming a concentration of 3 mg/dl, and average milk volumes of 750 and 600 ml in the first and second 6 months, respectively, the subcommittee estimates the average maternal losses are 22 and 18 mg/day. Allowing for variation in milk production (2 SDs, or 25%), and an intestinal absorption efficiency of 85%, a daily increment of 35 mg is recommended during the first 6 months of lactation and 30 mg thereafter. Infants and Children Breastfed infants with vitamin C intakes of 7 to 12 mg/day and bottle-fed infants with vitamin C intakes of 7 mg/
OCR for page 120
Page 120 day have been protected from scurvy (Goldsmith, 1961; Rajalakshmi et al., 1965; Van Eekelan, 1953). There are no other data on which to base an RDA. Accordingly, the subcommittee recommends 30 mg/ day during the first 6 months of life on the basis of the vitamin C content of milk, which should provide an adequate margin of safety. Premature infants may exhibit transient tyrosinemia (Irwin and Hutchins, 1976) and may therefore require a larger amount. The RDA beyond 6 months of age is gradually increased to the adult level. Other Considerations Usual daily dietary intakes of vitamin C (25 to 75 mg) can enhance the intestinal absorption of dietary nonheme iron by two- to fourfold (Cook and Monsen, 1977; Rossander et al., 1979). No effect on iron status as assessed from serum ferritin concentration was observed, however, in two studies in which vitamin C supplements were given with meals for several weeks (Cook et al., 1984). In one of these studies (Cook et al., 1984), intestinal adaptation to high intakes was excluded as a cause of apparent lack of change in iron stores. The significance of these observations in omnivorous, meat-eating subjects is unclear (Hallberg et al., 1987), but they do not exclude an effect of vitamin C on iron status in vegetarians or in other individuals with more limited intake of heme iron. Ascorbic acid may prevent the formation of carcinogenic nitrosamines by reducing nitrites. The ingestion of fruits and vegetables rich in vitamin C has been associated with a reduced incidence of some cancers, but there is no evidence that vitamin C is responsible for any such effects (NRC, 1989). Pharmacologic Intakes and Toxicity Daily intakes of ascorbic acid of 1 g or more have been reported to reduce the frequency and severity of symptoms of the common cold and other respiratory illnesses (Pauling, 1971). In controlled, double-blind trials, however, the effect of ascorbic acid was considerably smaller than had previously been reported (Anderson, 1975) or was not reproducible (Coulehan et al., 1976). Several reviewers (Chalmers, 1975; Dykes and Meier, 1975) have concluded that any benefits of large doses of ascorbic acid for these conditions are too small to justify recommending routine intake of large amounts by the entire population. Large doses of ascorbic acid have also been reported to lower serum cholesterol in some hypercholesterolemic subjects (Ginter et al.,
OCR for page 121
Page 121 1977), but these observations have not been confirmed by others (Peterson et al., 1975). A number of effects of large doses of ascorbic acid on other medical conditions have been reported, but there is no general agreement about their value. Many persons habitually ingest 1 g or more of ascorbic acid without developing apparent toxic manifestations. A number of adverse effects have, however, been reported (Barnes, 1975; Hornig and Moser, 1981; Rivers, 1987), and the risk of sustained ingestion of such amounts is unknown. Routine use of large doses of ascorbic acid is therefore not recommended. References Anderson, R., and P.T. Lukey, 1987. A biological role for ascorbate in the selective neutralization of extracellular phagocyte-derived oxidants. Ann. N.Y. Acad. Sci. 498:229-247. Anderson, R., and A. Theron. 1979. Effects of ascorbate on leucocytes. Part III. In vitro and in vivo stimulation of abnormal neutrophil motility by ascorbate. S. Afr. Med. J. 56:429-433. Anderson, T.W. 1975. Large-scale trials of vitamin C. Ann. N.Y. Acad. Sci. 258:498504. Baker, E.M., R.E. Hodges, J. Hood, H.E. Sauberlich, and S.C. March. 1969. Metabolism of ascorbic-l-14C acid in experimental human scurvy. Am. J. Clin. Nutr. 22:549-558. Baker, E.M., R.E. Hodges, J. Hood, H.E. Sauberlich, S.C. March, and J.E. Canham. 1971. Metabolism of 14C- and 3H-labeled L-ascorbic acid in human scurvy. Am. J. Clin. Nutr. 24:444-454. Barnes, M.J. 1975. Function of ascorbic acid in collagen metabolism. Ann. N.Y. Acad. Sci. 258:264-277. Bartley, W., H.A. Krebs, and J.R.P. O'Brien. 1953. Vitamin C Requirement of Human Adults. A Report by the Vitamin C Subcommittee of the Accessory Food Factors Committee. Medical Research Council Special Report Series No. 280. Her Majesty's Stationery Office, London. Bates, C.J., A.M. Prentice, A. Prentice, W.H. Lamb, and R.G. Whitehead. 1983. The effect of vitamin C supplementation on lactating women in Keneba, a West African rural community. Int. J. Vitam. Nutr. Res. 53:68-76. Brook, M., and J.J. Grimshaw. 1968. Vitamin C concentration of plasma and leukocytes as related to smoking habit, age, and sex of humans. Am. J. Clin. Nutr. 21:1254-1258. Byerley, L.O., and A. Kirksey. 1985. Effects of different levels of vitamin C intake on the vitamin C concentration in human milk and the vitamin C intakes of breast-fed infants. Am. J. Clin. Nutr. 81:665-671. Chalmers, T.C. 1975. Effects of ascorbic acid on the common cold: an evaluation of the evidence. Am. J. Med. 58:532-536. Cheng, L., M. Cohen, and H.N. Bhagavan. 1985. Vitamin C and the elderly. Pp. 157-185 in R.R. Watson, ed. CRC Handbook of Nutrition in the Aged. CRC Press, Boca Raton, Fla. Clemetson, C.A.B. 1980. Histamine and ascorbic acid in human blood. J. Nutr. 110:662-668.
OCR for page 122
Page 122 Cook, J.D., and E.R. Monson. 1977. Vitamin C, the common cold, and iron absorption. Am. J. Clin. Nutr. 30:235-241. Cook, J.D., S.S. Watson, K.M. Simpson, D.A. Lipschitz, and B.S. Skikne. 1984. The effect of high ascorbic acid supplementation on body iron stores. Blood 64:721726. Cooper, J.R. 1961. The role of ascorbic acid in the oxidation of tryptophan to 5hydroxytrlyptophan. Ann. N.Y. Acad. Sci. 92:208-211. Coulehan, J.L., S. Eberhard, L. Kapner, F. Taylor, K. Rogers, and P. Garry. 1976. Vitamin C and acute illness in Navajo school children. N. Engl. J. Med. 295:973977. Dawson, W., and G.B. West. 1965. The influence of ascorbic acid on histamine metabolism in guinea pigs. Br. J. Pharmacol. 24:725-734. Dykes, M.H.M., and P. Meier. 1975. Ascorbic acid and the common cold: evaluation of its efficacy and toxicity. J. Am. Med. Assoc. 231:1073-1079. Garry, P.J., J.S. Goodwin, W.C. Hunt, and B.A. Gilbert. 1982. Nutritional status in a healthy elderly population: vitamin C. Am. J. Clin. Nutr. 36:332-339. Garry, P.J., D.J. Vanderjagt, and W.C. Hunt. 1987. Ascorbic acid intakes and plasma levels in healthy elderly. Ann. N.Y. Acad. Sci. 498:90-99. Ginter, E. 1975. Ascorbic acid in cholesterol and bile acid metabolism. Ann. N.Y. Acad. Sci. 258:410-421. Ginter, E., O. Cerna, J. Budlovsky, V. Balaz, F. Hubra, V. Roch, and E. Sasko. 1977. Effect of ascorbic acid on plasma cholesterol in humans in a long-term experiment. Int. J. Vitam. Nutr. Res. 47:123-134. Glembotski, C.C. 1987. The role of ascorbic acid in the biosynthesis of the neuroendocrine peptides a-MSH and TRH. Ann. N.Y. Acad. Sci. 498:54-61. Goldsmith, G.A. 1961. Human requirements for vitamin C and its use in clinical medicine. Ann. N.Y. Acad. Sci. 92:230-245. Hallberg, L., M. Brune, and L. Rossander-Hulthén. 1987. Is there a physiological role of vitamin C in iron absorption? Pp. 324-332 in J.J. Burns, J.M. Rivers, and L.J. Machlin, eds. Third Conference on Vitamin C. Annals of the New York Academy of Sciences, Vol. 498. New York Academy of Sciences, New York. Hodges, R.E., E.M. Baker, J. Hood, H.E. Sauberlich, and S.C. March. 1969. Experimental scurvy in man. Am. J. Clin. Nutr. 22:535-548. Hodges, R.E.,. . Hood, J.E. Canham, H.E. Sauberlich, and E.M. Baker. 1971. Clinical manifestations of ascorbic acid deficiency in man. Am. J. Clin. Nutr. 24:432443. Hornig, D. 1975. Metabolism of ascorbic acid. World Rev. Nutr. Diet. 23:225-258. Hornig, D.H., and U. Moser. 1981. The safety of high vitamin C intakes in man. Pp. 225-248 in. .N. Counsell and D.H. Hornig, eds. Vitamin C (ascorbic acid). Applied Science, London. Hytten, F.E. 1980. Nutrition. Pp. 163-192 in F. Hytten and G. Chamberlain, eds. Clinical Physiology in Obstetrics. Blackwell, Oxford. Irwin, M.I., and B.K. Hutchins. 1976. A conspectus of research on vitamin C requirements of man. J. Nutr. 106:823-879. Jaffe, G.M. 1984. Vitamin C. Pp. 199-244 in L.J. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical, and Clinical Aspects. Marcel Dekker, New York. Johnson, C., C. Wotecki, and R. Murphy. 1984. Smoking, vitamin supplement use, and other factors affecting serum vitamin C. Fed. Proc. 43:666. Kallner, A. 1987. Requirement for vitamin C based on metabolic studies. Ann. N.Y. Acad. Sci. 498:418-423. Kallner, A., 1). Hartmann, and D. Hornig. 1977. On the absorption of ascorbic acid in man. Int. J. Vitam. Nutr. Res. 47:383-388.
OCR for page 123
Page 123 Kallner, A., 1). Hartmann, and D. Hornig. 1979. Steady-state turnover and body pool of ascorbic acid in man. Am. J. Clin. Nutr. 32:530-539. Kallner, A.B., I). Hartmann, and D.H. Hornig. 1 981. On the requirements of ascorbic acid in man: steady-state turnover and body pool in smokers. Am. J. Clin. Nutr. 34:1347-1355. Kallner, A., D. Hornig, and R. Pellikka. 1985. Formation of carlbon dioxide from ascorbate in man. Am. J. Clin. Nutr. 41:609-613. Khattab, A.K., S.A. al-Nagdy, K.A. Mourad, and H.I. el-Azghal. 1970. Foetal maternal ascorbic acid gradient in normal Egyptian subjects. J. Trop. Pediatr. 16:112115. La Du, B.N., and V.G. Zannoni. 1961. The role of ascorbic acid in tyrosine metabolism. Ann. N.Y. Acad. Sci. 92:175-191. Leibovitz, B., and B.V. Siegel. 1978. Ascorbic acid, neutrophil function, and the immune response. Int. J. Vitam. Nutr. Res. 48:159-164. Levenson, S.M., G. Manner, and E. Seifter. 1971. Aspects of the adverse effects of dysnutrition on wound healing. Pp. 132-156 in S. Margen, ed. Progress in Human Nutrition, Vol. 1. AVI Publishing, Westport, Conn. Levin, E.Y., B. Levenberg, and S. Kaufman. 1960. The enzymatic conversion of 3,4dihydroxyphenylethylamine to norepinephrine. J. Biol. Chem. 235:2080-2086. Marston, R., and N. Raper. 1987. Nutrient content of the U.S. food supply. Natl. Food Rev. Winter-Spring, NFR-36: 18-23. Morse, E.H., R.P. Clark, D.E. Keyser, S.B. Merrow, and D.E. Bee. 1975. Comparison of the nutritional status of pregnant adolescents with adult pregnant women. 1. Biochemical findings. Am. J. Clin. Nutr. 28:1000-1013. Moser, U. 1987.Uptake of ascorbic acid by leukocytes. Ann. N.Y. Acad. Sci. 498:200215. Myllyla, R., E.R. Kuutti-Savolainen, and K.I. Kivirikko. 1978. The role of ascorbate in the prolyl hydroxylase reaction. Biochem. Biophys. Res. Commun. 83:441448. Newton, H.M.V., C.J. Schorah, N. Habibzadeh, D.B. Morgan, and R.P. Hullin. 1985. The cause and correction of low blood vitamin C concentrations in the elderly. Am. J. Clin. Nutr. 42:656-659. NRC (National Research Council). 1982. Diet, Nutrition, and Cancer. Report of the Committee on Diet, Nutrition, and Cancer, Assembly of Life Sciences. National Academy Press, Washington, D.C. 496 pp. NRC (National Research Council). 1989. Diet and Health: Implications for Reducing Chronic Disease Risk. Report of the Committee on Diet and Health, Food and Nutrition Board. National Academy Press, Washington, D.C. 750 pp. Pauling, L. 1971. The significance of the evidence about ascorbic acid and the common cold. Proc. Natl. Acad. Sci. U.S.A. 68:2678-2681. Pelletier, 0. 1975. Vitamin C and cigarette smokers. Ann. N.Y. Acad. Sci. 258:156168. Peterson, V.E., P.A. Crapo, J. Weininger, H. Ginsberg, and J. Olefsky. 1975. Quantification of plasma cholesterol and triglyceride levels in hypercholesterolemic subjects receiving ascorbic acid supplements. Am. J. Clin. Nutr. 28:584-587. Rajalakshmi, R., A.D. Doedhar, and C.V. Ramarkrishnan. 1965. Vitamin C secretion during lactation. Acta Paediatr. Scand. 54:375-382. Rivers, J.M. 1987. Safety of high-level vitamin C ingestion. Ann. N.Y. Acad. Sci. 498:445-454. Rivers, J.M., and M.M. Devine. 1975. Relationships of ascorbic acid to pregnancy, and oral contraceptive steroids. Ann. N.Y. Acad. Sci. 258:465-482.
OCR for page 124
Page 124 Rossander, L., L.. Hallberg, and E. Bjorn-Rasmussen. 1979. Absorption of iron from breakfast meals. Am. J. Clin. Nutr. 32:2484-2489. Sabry, J.H., K.H. Fisher, and M.I,. Dodds. 1958. Human utilization of dehydroascorbic acid. J. Nutr. 64:457-466. Salmenpera, L. 1984. Vitamin C nutrition during prolonged lactation: optimal in infants while marginal in some mothers. Am. J. Clin. Nutr. 40:1050-1056. Sauberlich, H.E. 1981. Ascorbic acid.(vitamin C). Pp. 673-684 in R.F. Babbe, ed. Clinics in Laboratory Medicine, Vol. 1. Symposium on laboratory Assessment of Nutritional Status. W.B. Saunders, Philadelphia. Sauberlich, H.E., J.H. Skala, and R.P. Dowdy. 1974. Pp. 13-22 in Laboratory Tests for the Assessment of Nutritional Status. CRC Press, Cleveland, Ohio. Sauberlich, H.E.. M.J. Kretsch, P.C. Taylor, H.L. Johnson, and J.H. Skalam. In press. Ascorbic acid and erythorbic acid metabolism in nonpregnant women. Am. J. Clin. Nutr. Schectman, G., J.C. Byrd, and H.W. Gruchow. 1989. The influence of smoking on vitamin C status in adults. Am. J. Public Health 79:158-162. Smith, J.L., and R.E. Hodges. 1987. Serum levels of vitamin C in relation to dietary and supplemental intake of vitamin C in smokers and nonsmokers. Ann. N.Y. Acad. Sci. 498:144-152. Sneed, S.M., C. Zane, and M.R. Thomas. 1981. The effects of ascorbic acid, vitamin B6, vitamin B12, and folic acid supplementation on the breast milk and maternal nutrition status of low socioeconomic lactating women. Am. J. Clin. Nutr. 34:1338-1346. Stevenson, N.R. 1974. Active transport of L-ascorbic acid in the human ileum. Gastroenterology 67:952-956. Stewart, M.L., J.T. McDonald, A.S. Levy, R.E. Schucker, and D.P. Henderson. 1985. Vitamin/mineral supplement use: a telephone survey of adults in the United States. Am. J. Diet. Assoc. 85:1585-1590. Stokes, P.L.., V. Melikian, R.L. Leeming, H. Portman-Graham, J.A. Blair, and W.T. Cooke. 1975. Folate metabolism in scurvy. Am. J. Clin. Nutr. 28:126-129. Tarjan, R., M. Kramer, K. Szoke, K. Lindner, T. Szarvas, and E. Dworshak. 1965. The effect of different factors on the composition of human milk. II. The composition of human milk during lactation. Nutr. Dieta 7: 136-154. USDA (U.S. Department of Agriculture). 1984. Nationwide Food Consumption Survey. Nutrient Intakes: Individuals in 48 States, Year 1977-78. Report No. 1-2. Consumer Nutrition Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 439 pp. USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp. USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey. Continuing Survey of Food Intakes of Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 I)ays, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 182 pp. Van Fekelen, M. 1953. Occurrence of vitamin C in foods. Proc. Nutr. Soc. 12:228232. Wilbur, V.A., and B.L. Walker. 1977. Dietary ascorbic acid and the time of response of the guinea pig to ACTH administration. Nutr. Rep. Int. 16:789-794. Woodruff, C.W. 1975. Ascorbic acid¬scurvy. Prog. Food Nutr. Sci. 1:493-506.
OCR for page 125
Page 125 THIAMIN Thiamin as thiamin pyrophosphate (TPP) is a coenzyme required for the oxidative decarboxylation of a-keto acids and for the activity of transketolase in the pentose phosphate pathway. At usual levels in the diet, thiamin is rapidly absorbed, largely in the proximal small intestine. It is excreted in the urine, both intact as thiamin acetic acid and as metabolites of its cleavage products-the pyrimidine and thiazolic moieties (Hansen and Munro, 1970; McCormick, 1988; Ziporin et al., 1965). General Signs of Deficiency Thiamin deficiency is associated with abnormalities of carbohydrate metabolism related to a decrease in oxidative decarboxylation. During severe deficiencies, plasma and tissue levels of pyruvate are increased. Reduced TPP saturation of erythrocyte transketolase has also been observed in animals and humans fed diets low in thiamin (Sauberlich et al., 1979). Clinical signs of deficiency have been noted when less than 7% (70 µg) of a 1 mg dose of thiamin is excreted in the urine in a dose-retention test (Horwitt et al., 1948). The clinical condition associated with the prolonged intake of a diet low in thiamin is traditionally called beriberi, whose primary symptoms involve the nervous and cardiovascular systems. The characteristic signs include mental confusion, anorexia, muscular weakness, ataxia, peripheral paralysis, ophthalmoplegia, edema (wet beriberi), muscle wasting (dry beriberi), tachycardia, and enlarged heart (Horwitt et al., 1948; Inouye and Katsura, 1965; Platt, 1967; Williams et al., 1942). In even a moderate deficiency, addition of a glucose load (100 g) can raise the plasma levels of lactic and pyruvic acids above those noted in control subjects (Williams et al., 1943), and may increase liver and heart muscle glycogen (Hawk et al., 1954). Indeed, carbohydrate loading can be an important precipitant of the thiaminresponsive neuropathy characteristic of the Wernicke-Korsakoff syndrome (Watson et al., 1981). Moreover, the development of wet beriberi in both its acute and chronic forms is favored by a high carbohydrate intake and increased physical activity (Burgess, 1958; Platt, 1958), a finding consistent with the fact that addition of even a 1-minute mild exercise period 60 minutes after a glucose load increases the differences in plasma lactic and pyruvic acids between controls and thiamin-depleted subjects (Horwitt et al., 1948). In infants, deficiency symptoms appear more suddenly than they do in adults and are usually more severe, often involving cardiac failure (McCormick, 1988).
OCR for page 163
Page 163 newborns are double that of their mothers (Giugliani et al., 1985). Normally, maternal body stores are sufficient to meet the needs of pregnancy, and it is unlikely that any increment in vitamin B12 intake is needed. An additional allowance of 0.2 µg/day can, however, be justified. Vitamin B12 in human milk parallels the concentration in serum. At 6 months postpartum, 0.6 µg/liter was found in the milk of wellnourished women in the United States (Thomas et al., 1980). This would mean a loss of 0.45 µg in 750 ml of human milk, or 0.56 µg/ day at the upper level of production. An additional allowance of 0.6 µg/day is recommended for lactating women. Symptoms of vitamin B12 deficiency have been observed in some breastfed infants of women who are strict vegetarians (Higginbottom et al., 1978; Specker et al., 1988). Pregnant and lactating women adhering to diets devoid of animal-source foods should be advised to take supplementary vitamin B12 at RDA levels (i.e., 2.2 and 2.6 µg/ day, respectively). Infants and Children Since overt vitamin B12 deficiency does not occur in infants breastfed by women with adequate serum vitamin B12 levels (Lampkin et al., 1966), and vitamin B12-deficient infants of B12-deficient vegetarian mothers show a full therapeutic response to oral doses of 0.1 µg/day (Jadhav et al., 1962), the RDA for the young infant has been set at 0.3 µg/day (i.e., 0.05 µg/kg body weight) to allow a substantial margin for storage. The RDAs for older infants and preadolescent children have been based on progressive increases with increasing body size (at 0.05 µg/kg body weight) until the RDA for adults (2 µg) is reached. Excessive Intakes and Toxicity No clear toxicity has been reported from daily oral ingestion of up to 100 µg. Similarly, no benefit has been reported in nondeficient people from such large quantities. Changes in Vitamin B12 Allowances Compared to Ninth Edition The present RDAs for vitamin B12 are one-third to one-half lower than those given in the ninth edition. They are, however, approximately double the safe level of intake of vitamin B12 established by the FAO (1988). The difference in recommendations based on the same body of evidence reflects the present subcommittee's conserv-
OCR for page 164
Page 164 ative stance on the desirability of maintaining a substantial body pool of vitamin B12. References Adams, J.F. 1962. The measurement of the total assayable vitamin Bl2 in the body. P. 397 in C. Heinrich, ed. Vitamin B12 und Intrinsic Faktor. Ferdinand Enke, Stuttgart, Federal Republic of Germany. Albert, M.J., V.I. Mathan, and S.J. Baker. 1980. Vitamin B12 synthesis by human small intestinal bacteria. Nature 283:781-782. Armstrong, B.K., R.E. Davis, D.J. Nicol, A.J. van Merwyk, and C.J. Larwood. 1974. Hematological, vitamin B12, and folate studies on Seventh-Day Adventist vegetarians. Am. J. Clin. Nutr. 27:712-718. Baker, S.J., and V.I. Mathan. 1981. Evidence regarding the minimal daily requirement of dietary vitamin B12. Am. J. Clin. Nutr. 34:2423-2433. Carmel, R., and D.S. Karnaze. 1985. The deoxyuridine suppression test identifies subtle cobalamin deficiency in patients without typical megaloblastic anemia. J. Am. Med. Assoc. 253:1284-1287. Chanarin, 1. 1979. The Megaloblastic Anaemias, 2nd ed. Blackwell, Oxford. Dolphin, D., ed. 1982. B12 Vol. 2. Biochemistry and Medicine. John Wiley & Sons, New York. 505 pp. FAO (Food and Agriculture Organization). 1988. Requirements of Vitamin A, Iron, Folate, and Vitamin B12. Report of a Joint FAO/WHO Expert Consultation. FAO Food and Nutrition Series No. 23. Food and Agriculture Organization, Rome. 107 pp. Garry, P.J., J.S. Goodwin, and W.C. Hunt. 1984. Folate and vitamin B12 status in a healthy elderly population. J. Am. Geriatr. Soc. 32:719-726. Gimsing, P., and E. Nex. 1983. The forms of cobalamin in biological materials. Pp. 7-30 in C.A. Hall, ed. The Cobalamins. Churchill Livingstone, Edinburgh. Giugliani, E.R.J., S.M. Jorge, and A.L. Gonçalves. 1985. Serum vitamin B12levels in parturients, in the intervillous space of the placenta and in full-term newborns and their interrelationships with folate levels. Am. J. Clin. Nutr. 41:330-335. Hall, C.A., 1964. Long term excretion of Co57-vitamin B12 and turnover within plasma. Am. J. Clin. Nutr. 14:156-162. Heinrich, H.C . 1964. Metabolic basis of the diagnosis and therapy of vitamin B12 deficiency. Semin. Hematol. 1:199-249. Herbert, V. 1968. Nutritional requirements for vitamin B12 and folic acid. Am. J. Clin. Nutr. 21:743-752. Herbert, V. 1984. Vitamin B12. Pp. 347-364 in Nutrition Reviews' Present Knowledge in Nutrition, 5th ed. The Nutrition Foundation, Washington, D.C. Herbert, V. 1985. Biology of disease: megaloblastic anemias. Lab. Invest. 52:3-19. Herbert, V.D., and N. Colman. 1988. Folic acid and vitamin B12. Pp. 388-416 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia. Herbert, V., G. Drivas, C. Manusselis, M. Mackler, J. Eng, and E. Schwartz. 1984. Are colon bacteria a major source of cobalamin analogues in human tissues? 24h human stool contains only about 5 µg of cobalamin but about 100 µg of apparent analogue (and 200 µg folate). Trans. Assoc. Amer. Phys. 97:161-171. Herzlich, B., G. Drivas, and V. Herbert. 1985. A new serum test which may reliably diagnose vitamin B12 deficiency: total desaturation of serum transcobalamin II (TC II). Clin. Res. 33:605A.
OCR for page 165
Page 165 Heyssel, R.M., R.C. Bozian, W.J. Darby, and M.C. Bell. 1966. Vitamin B12 turnover in man. The assimilation of vitamin B12 from natural foodstuff by man and estimates of minimal dietary requirements. Am. J. Clin. Nutr. 18:176-184. Higginbottom, M.C., L. Sweetman, and W.L. Nuhan, 1978. A syndrome of methylmalonic aciduria, homocystinuria, megaloblastic anemia and neurologic abnormalities in a vitamin B12-deficient breast-fed infant of a strict vegetarian. N. Eng. J. Med. 299:317-323. Jadhav, M., J.K.G. Webb, S. Vaishnava, and S.J. Baker. 1962. Vitamin B12 deficiency in Indian infants: a clinical syndrome. Lancet 2:903-907. Lampkin, B.D., N.A. Shore, and D. Chadwick. 1966. Megaloblastic anemia of infancy secondary to maternal pernicious anemia. N. Engl. J. Med. 274:1168-1171. Lindenbaum, J., E.B. Healton, D.G. Savage, J.C.M. Brust, T.J. Garrett, E.R. Podell, P.D. Marcell, S.P. Stabler, and R.H. Allen. 1988. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N. Engl. J. Med. 318:1720-1728. Linnell, J.C., A.V. Hoffbrand, H.A.A. Hussein, I.J. Wise, and D.M. Matthews. 1974. Tissue distribution of coenzyme and other forms of vitamin B12 in control subjects and patients with pernicious anemia. Clin. Sci. Mol. Med. 46:163-172. Reizenstein, P.C., G. Ek, and C.M.E. Matthews. 1966. Vitamin B12 kinetics in man. Implications of total-body B 12 determinations, human requirements, and normal and pathological cellular B12 uptake. Phys. Med. Biol. 2:295-306. Specker, B.L., D. Miller, E.J. Norman, H. Greene, and K.C. Hayes. 1988. Increased urinary methylmalonic acid excretion in breast-fed infants of vegetarian mothers and identification of an acceptable dietary source of vitamin B12. Am. J. Clin. Nutr. 47:89-92. Stewart, J.S., P.D. Roberts, and A.V. Hoffbrand. 1970. Response of dietary vitaminB12 deficiency to physiological oral doses of cyanocobalamin. Lancet 2:542-545. Sullivan, L.W., and V. Herbert. 1965. Studies on the minimum daily requirements for vitamin B12 Hematopoietic responses to 0.1 microgram of cyanocobalamin or coenzyme B12 and comparison of their relative potency. N. Engl. J. Med. 272:340-346. Thomas, M.R., S.M. Sneed, C. Wei, P.A. Nail, M. Wilson, and E.E. Sprinkle I11. 1980. The effects of vitamin C, vitamin B6, vitamin B12, folic acid, riboflavin, and thiamin on the breast milk and maternal status of well-nourished women at 6 months postpartum. Am. J. Clin. Nutr. 33:2151-2156. USDA (U.S. Department of Agriculture). 1986. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Men 19-50 Years, 1 Day, 1985. Report No. 85-3. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 94 pp. USDA (U.S. Department of Agriculture). 1987. Nationwide Food Consumption Survey Continuing Survey of Food Intakes by Individuals: Women 19-50 Years and Their Children 1-5 Years, 4 Days, 1985. Report No. 85-4. Nutrition Monitoring Division, Human Nutrition Information Service. U.S. Department of Agriculture, Hyattsville, Md. 182 pp. BIOTIN Biotin is a sulfur-containing vitamin essential for several species, including humans. It is a component of various foods and is synthesized in the lower gastrointestinal tract by microorganisms and some
OCR for page 166
Page 166 fungi. The chemically related compounds oxybiotin and biocytin are also biologically active for some species. (For a more detailed discussion of the role of biotin in human nutrition, see Bonjour, 1985.) Biotin is an integral part of enzymes that transport carboxyl units and fix carbon dioxide in animal tissue. The conversion of biotin to the active coenzyme is dependent on magnesium and adenosine triphosphate (ATP) (Bonjour, 1984). Two biotin enzymes, pyruvate carboxylase and acetyl-coenzyme A (CoA) carboxylase, play essential roles in gluconeogenesis and fatty acid synthesis, respectively. Extensive fatty infiltration of the liver and kidney, hypoglycemia, and depressed gluconeogenesis in the liver of biotin-deficient chicks provide further evidence of the importance of biotin in carbohydrate and lipid metabolism (Bannister, 1976). Two other biotin enzymes, propionyl-CoA carboxylase and 3-methylcrotonyl CoA carboxylase, are required for propionate metabolism and the catabolism of branchedchain amino acids. Low activity of biotin enzymes results in the urinary excretion of organic acids (the nature of which is determined by the metabolic step that is blocked), skin rash, and hair loss. Multiple carboxylase deficiencies are usually due to defective holocarboxylase synthetase, which is required for the conversion of inactive apocarboxylase to form active carboxylases through the addition of biotin (Sweetman, 1981). This inborn error of metabolism can be overcome by large doses (10 to 40 mg) of biotin (Wolf and Feldman, 1982). Another genetic defect results in a deficiency of biotinidase, an enzyme that releases protein-bound biotin and cleaves biocytin so that the biotin can be rectcled (Wolf and Feldman, 1982). General Signs of Deficiency In adult humans ad most animals, biotin deficiency can be produced by the ingestion of large amounts of avidinthe biotin-binding glycoprotein found only in raw egg white (Baugh et al., 1968). Biotin deficiency is characterized by anorexia, nausea, vomiting, glossitis, pallor, mental depression, alopecia and a dry scaly dermatitis, and an increase in serum cholesterol and bile pigments. Symptoms of hair loss have been observed in two adults on long-term total parenteral nutrition (TPN) without added biotin following extensive gut resection, which decreases the amount produced by intestinal biosynthesis (Innis and Allardyce, 1983), and in children on TPN (McClain, 1983). Symptoms were alleviated with 200 to 300 µg of biotin per day. Hair loss in an infant on TPN for 5 months was reversed by administering 10 mg of biotin (Mock et al., 1981). Evidence indicates that the seborrheic dermatitis of infants under 6 months of age is due to nu-
OCR for page 167
Page 167 tritional biotin deficiency. In such cases, blood levels and urinary excretion of the vitamin are depressed. Prompt improvement occurs with therapeutic doses of the vitamin-approximately 5 mg/day (Bonjour, 1985). Dietary Sources and Usual Intakes The best sources of biotin are liver (100 to 200 µg/100 g), egg yolk (16 µg/100 g), soy flour (60 to 70 µg/100 g), cereals (3 to 30 µg/100 g), and yeast (100 to 200 µg/100 g). Fruit and meat are poor sources, each containing from 0.6 to 2.3 µg of biotin per 100 g (Guilarte, 1985; Hoppner and Lampi, 1983; Paul and Southgate, 1978). The bioavailability of biotin varies considerably, depending on whether it is present in the biologically available unbound form as it is in most foods or in the unavailable bound form in wheat. Information on the biotin content of food provided in tables of food composition is not complete. As a result, intake of biotin is seldom considered in nutrient consumption studies. In a study by Marshall et al. (1985), biochemical analyses of duplicate samples of U.S. diets indicated that biotin intakes were 28 to 42 µg/day. Dietary biotin consumed in Western Europe is estimated to range from 50 to 100 µg/day (Bonjour, 1985). Intestinal Synthesis Biotin is synthesized by intestinal microorganisms, but the extent of its availability for absorption is not established. The combined urinary and fecal excretion of biotin can exceed the dietary intake. Thus, fecal excretion apparently comprises biotin synthesized in the gut as well as unabsorbed dietary biotin. The urine contains biotin absorbed from the diet, from body stores, and, possibly, from intestinal synthesis. Urinary values range from less than 6 to 50 µg/day (Baker, 1985; Marshall et al., 1985). Information on blood levels is so variable that it is of little diagnostic value. Men whose diets contained 28 to 42 µg/day had serum biotin levels ranging from 627 to 737 pg/ml (Marshall et al., 1985). Serum, urinary, and dietary biotin were correlated. Estimated Safe and Adequate Daily Dietary Intakes Adults The lack of definitive studies of biotin requirements make it difficult to estimate an allowance. A daily dose of 60 µg has maintained adults on total parenteral nutrition symptom-free for 6
OCR for page 168
Page 168 months in the absence of meaningful intestinal synthesis (Innis and Allardyne, 1983). Diets supplying 28 to 42 µg of biotin per day were associated with urinary excretion of 20 to 24 µg/day in volunteers. There was no indication of inadequate status in the subjects. In view of the incomplete knowledge of the bioavailability of biotin in foods and of the uncertain contribution of intestinal synthesis to the total intake, a range of 30 to 100 µg is provisionally recommended for adults. This range is lower than that recommended in the previous edition of the RDA, because improved analytical methods for biotin have reduced the estimates of daily intakes compatible with good health. Pregnancy and Lactation Blood biotin levels are significantly lower in pregnant than in nonpregnant women and fall progressively throughout gestation. However, low blood biotin levels are not associated with low birth weight infants (Bonjour, 1984). Thus, no increment for pregnancy is recommended. Data are not sufficient for a recommendation to be made for lactation. Infants and Children The biotin content of human milk, all in the free, available form, has been variously reported as 3 to 4.7 (Goldsmith et al., 1982), 7 (Paul and Southgate, 1978), and 20 µg/ liter (Heard et al., 1987). Ifa daily milk consumption is assumed to be 750 ml, the intake of infants would range from 2 to 15 µg/day, depending on which analysis is accepted. An intake of 10 and 15 µg/ day is tentatively recommended for formula-fed infants during the first and second 6 months, respectively, in agreement with the recommendations of the American Academy of Pediatrics for biotin in infant formulas (AAP, 1976). Recommended intakes for children and adolescents are gradually increased to adult levels above age 11. Excessive Intakes and Toxicity There have been no reports of toxicity associated with intakes as high as 10 mg daily (LSRO, 1978). References AAP (American Academy of Pediatrics). 1976. Commentary on breast feeding and infant formulas, including proposed standards for formulas. Pediatrics 57:278285. Baker, H. 1985. Assessment of biotin status: clinical implications. Ann. N.Y. Acad. Sci. 447:129-132.
OCR for page 169
Page 169 Bannister, D.W. 1976. The biochemistry of fatty liver and kidney syndrome. Biochem. J. 156:167-173. Baugh, C.M.,J.W. Malone, and C.E. Butterworth, Jr. 1968. Human biotin deficiency. A case history of biotin deficiency induced by raw egg consumption in a cirrhotic patient. Am.J. Clin. Nutr. 21:173-182. Bonjour, J.-P. 1984. Biotin. Pp. 403-435 in L.J. Machlin, ed. Handbook of Vitamins: Nutritional, Biochemical and Clinical Aspects. Marcel Dekker, New York. Bonjour, J.-P. 1985. Biotin in human nutrition. Ann. N.Y. Acad. Sci. 447:97-104. Goldsmith, S.J., R.R. Eitenmiller, R.M. Feeley, H.M. Barnhart, and F.C. Maddox. 1982. Biotin content of human milk during early lactational states. Nutr. Res. 2:579-583. Guilarte, T.R. 1985. Analysis of biotin levels in selected foods using a radiometricmicrobiological method. Nutr. Rep. Int. 32:837-845. Heard, G.S., J.B. Redmond, and B. Wolf. 1987. Distribution and bioavailability of biotin in human milk. Fed. Proc. 46:897. Hoppner, K., and B. Lampi. 1983. The biotin content of breakfast cereals. Nutr. Rep. Int. 28:793-798. Innis, S.M., and D.B. Allardyce. 1983. Possible biotin deficiency in adults receiving long-term total parenteral nutrition. Am. J. Clin. Nutr. 37:185-187. LSRO (Life Sciences Research Office). 1978. Evaluation of the Health Aspects of Biotin as a Food Ingredient. SCOGS 92. Federation of American Societies for Experimental Biology, Bethesda, Md. 16 pp. Marshall, M.W., J.T. Judd, and H. Baker. 1985. Effects of low and high-fat diets varying in ratio of polyunsaturated to saturated fatty acids on biotin intakes and biotin in serum, red cells and urine of adult men. Nutr. Res. 5:801-814. McClain, C.J. 1983. Biotin deficiency complicating parenteral alimentation. J. Am. Med. Assoc. 250:1028. Mock, D.M., A.A. deLorimer, W.M. Liebman, L. Sweetman, and H. Baker. 1981. Biotin deficiency: an unusual complication of parenteral alimentation. N. Engl. J. Med. 304:820-823. Paul, A.A., and D.A.T. Southgate. 1978. The Composition of Foods. Her Majesty's Stationery Office, London. Sweetman, L. 1981. Two forms of biotin-responsive multiple carboxylase deficiency. J. Inherited Metab. Dis. 4:53-54. Wolf, B., and G.L. Feldman. 1982. The biotin-dependent carboxylase deficiencies. Am. J. Hum. Genet. 34:699-716. PANTOTHENIC ACID Pantothenic acid, a B-complex vitamin, plays its primary physiological roles as a component of the coenzyme A molecule and within the 4'-phosphopantetheine moiety of the acyl carrier protein of fatty acid synthetase, which serves in acyl-group activation and transfer reactions (McCormick, 1988). These reactions are important in the release of energy from carbohydrates; in gluconeogenesis; in the synthesis and degradation of fatty acids; in the synthesis of such vital compounds as sterols and steroid hormones, porphyrins, and acetylcholine; and in acylation reactions in general (Abiko, 1975; Goldman and Vagelos, 1964).
OCR for page 170
Page 170 General Signs of Deficiency Dietary deficiency of pantothenic acid in animals results in a broad spectrum of biochemical defects. These manifest themselves in a variety of abnormalities: retarded growth rates in young animals; infertility, abortion, and frequent neonatal deaths; abnormalities of skin, hair, pigmentation, and feathers; neuromuscular disorder; gastrointestinal malfunction; adrenal cortical failure; and sudden death (Novelli, 1953). Evidence of dietary deficiency has not been clinically recognized in humans, but deficiency symptoms have been produced by administering a metabolic antagonist, w-methylpantothenic acid (Hodges et al., 1959), and more recently by feeding subjects a semisynthetic diet virtually free of pantothenic acid for 9 weeks (Fry et al., 1976). The young adult males studied by Fry and colleagues appeared listless and complained of fatigue after 9 weeks on the pantothenic acidfree diet; blood and urinary levels of this nutrient were significantly lower compared to controls. Naturally occurring pantothenic acid deficiencies have not been reliably documented. However, they have been implicated in the ''burning feet" syndrome observed among prisoners of war and among malnourished individuals in the Far East, since the symptoms appeared to respond to pantothenic acid preparations and not to other members of the vitamin B complex (Glusman, 1947). Dietary Sources and Usual Intakes Pantothenic acid is widely distributed among foods. It is especially abundant in animal tissues, whole grain cereals, and legumes. Smaller amounts are found in milk, vegetables, and fruits. Synthesis of pantothenic acid by intestinal microflora has been suspected, but the amount produced and the availability of the vitamin from this source are unknown. The apparent absence of pantothenic acid deficiency in the human population may therefore be attributed both to its ubiquity in foods and to possible additional contributions front intestinal flora. The usual intake of pantothenic acid in the United States has been reported to range from 5 to 10 mg/day (Fox and Linkswiler, 1961; Fry et al., 1976). In two more recent studies, investigators reported average intakes of approximately 6 mg/day (Srinivasan et al., 198l; Tarr et al., 1981). Srinivasan and colleagues conducted a study in an elderly population, and showed no difference in intakes between institutionalized and noninstitutionalized subjects. In another study,
OCR for page 171
Page 171 Johnson and Nitzke (1975) found that diets consumed by a group of low-income women provided about 4 mg of pantothenic acid per day. In a group of 7- to 9-year-old children, diets that met the recommended allowances for all other nutrients provided 4 to 5 mg of pantothenic acid daily (Pace et al., 1961). In a small group of pregnant, postpartum, and nonpregnant teenagers, the calculated dietary intakes were lower, ranging from 1.1 to 7.2 mg/day (Cohenour and Calloway, 1972). Estimated Safe and Adequate Daily Dietary Intakes Adults Urinary excretion generally correlates with dietary intake of pantothenic acid, although individual variation is large. Adults who consume 5 to 7 mg of pantothenic acid daily excrete 2 to 7 mg/ day in the urine and 1 to 2 mg/day in the feces (Fox and Linkswiler, 1961). In experimental diets, 100 mg/day has generally been selected for supplementation. At this level, subjects were found to excrete 5 to 7 mg/day in the urine (Fry et al., 1976). This evidence suggests that an intake of 4 to 7 mg/day should be safe and adequate for adults. The subcommittee concluded that there is insufficient evidence to set an RDA for pantothenic acid. Pregnancy and Lactation The amounts of pantothenic acid secreted in milk can represent a large fraction of the usual dietary intake. Nonetheless, the absence of reports of pantothenic acid deficiency either in pregnant or lactating women indicates that present levels of consumption from the diet (e.g., more than 5 mg/day), possibly supplemented by intestinal microfloral synthesis, is adequate to cover the needs of pregnancy and lactation. Thus, the suggested intake for nonpregnant adults would appear to be adequate for this group. Infants, Children, and Adolescents Reports of the mean pantothenic acid content of human milk have varied from 1 mg/day (Deodhar and Ramakrishnan, 1960) to 5 mg/day (Johnston et al., 1981), based on an average daily milk production of 750 ml. Song et al. (1984) reported a mean pantothenic acid content at 2 and 12 weeks postpartum of 2.57 mg/liter and 2.55 mg/liter, respectively, for mothers of full-term infants. These values are equivalent to approximately 1.9 mg/day in 750 ml of milk. The differences in the various reports may represent differences in maternal intakes or in analytical techniques. There are no reports of pantothenic acid deficiency in infants, suggesting that intake is adequate. The provisional recommended
OCR for page 172
Page 172 allowance is set at 2 to 3 mg/day for infants. Recommended intakes for children and adolescents are gradually increased to adult levels by age 11. Excessive Intakes and Toxicity Evidence suggests that pantothenic acid is relatively nontoxic. As much as 10 g of calcium pantothenate per day was given to young men for 6 weeks with no toxic symptoms reported (Ralli and Dumm, 1953). Other studies indicate that daily doses of 10 to 20 g may result in occasional diarrhea and water retention (Sebrell and Harris, 1954). References Abiko, Y. 1975. Metabolism of coenzyme A. Pp. 1-25 in D.M. Greenberg, ed. Metabolism of Sulfur Compounds, Vol. 7. Metabolic Pathways. Academic Press, New York. Cohenour, S.H., and D.H. Calloway. 1972. Blood, urine and dietary panthothenic acid levels of pregnant teenagers. Am. J. Clin. Nutr. 25:512-517. Deodhar, A.D., and C.V. Ramakrishnan. 1960. Studies on human lactation (relation between the dietary intake of lactating women and the chemical composition of milk with regard to vitamin content). J. Trop. Pediatr. 6:44-47. Fox, H.M., and H. Linkswiler. 1961. Pantothenic acid excretion on three levels of intake. J. Nutr. 75:45:1-454. Fry, P.C., H.M. Fox, and H.G. Tao. 1976. Metabolic reponse to a pantothenic acid deficient diet in humans. J. Nutr. Sci. Vitaminol. 22:339-346. Glusman, M. 1947. Syndrome of "burning feet" (nutritional melalgia) as manifestation of nutritional deficiency. Am. J. Med. 3:211-223. Goldman, P., and P.R. Vagelos. 1964. Acyl-transfer reactions (CoA-structure, function). Pp. 71-92 in M. Florkin and E. H. Stotz, eds. Comprehensive Biochemistry, Vol. 15. Group-Transfer Reactions. Elsevier, Amsterdam. Hodges, R.E., W.B. Bean, M.A. Ohison, and B. Bleiler. 1959. Human pantothenic acid deficiency produced by omega-methylpantothenic acid. J. Clin. Invest. 38:1421-1425. Johnson, N.E., and S. Nitzke. 1975. Nutritional adequacy of diets of a selected group of low-income women: identification of some related factors. Home Econ. Res. J. 3:241-246. Johnston, L., L.. Vaughan, and H.M. Fox. 1981. Pantothenic acid content of human milk. Am. J. Clin. Nutr. 34:2205-2209. McCormick, D.B. 1988. Pantothenic acid. Pp. 383-387 in M.E. Shils and V.R. Young, eds. Modern Nutrition in Health and Disease, 7th ed. Lea & Febiger, Philadelphia. Novelli, G.D. 1953. Metabolic significance of B-vitamins: Symposium; Metabolic functions of pantothenic acid. Physiol. Rev. 33:525-543. Pace, J.K., L.B. Stier, D.D. Taylor, and P.S. Goodman. 1961. Metabolic patterns in preadolescent children. V. Intake and urinary excretion of pantothenic acid and of folic acid. J. Nutr. 74:345-351. Ralli, E.P., and M.E. Dumm. 1953. Relation of pantothenic acid to adrenal cortical function. Vitam. Horm. 11:133-158.
OCR for page 173
Page 173 Sebrell, W.H., Jr., and R.S. Harris, eds. 1954. Pantothenic acid. Pp. 591-694 in The Vitamins: Chemistry, Physiology, Pathology, Vol. 2. Academic Press, New York. Srinivasan, V., N. Christensen, B.W. Wyse, and R.G. Hansen. 1981. Pantothenic acid nutritional status in the elderly-institutionalized and noninstitutionalized. Am. J. Clin. Nutr. 34:1736-1742. Song, W.O., G.M. Chan, B.W. Wyse, and R.G. Hansen. 1984. Effect of pantothenic acid status on the content of the vitamin in human milk. Am. J. Clin. Nutr. 40:317-324. Tarr, J.B., T. Tamura, and E.L.R. Stokstad. 1981. Availability of vitamin B6 and pantothenate in an average American diet in man. Am. J. Clin. Nutr. 34:13281337.
Representative terms from entire chapter: