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Pantothenic Acic! Williams (1939) first isolated pantothenic acid as a growth factor for yeast. The vitamin was also investi- gated as a growth-promoting factor for lactic acid bacte- ria. Pantothenic acid is widely distributed in biological materials. Subsequent to its isolation as a microbial growth factor, it was shown that pantothenic acid is identical to an antidermatitis factor for chicks and a growth-promoting factor for rats (Fox, 1984; Olson, 1984~. The presence of pantothenic acid as a component of coenzyme A (L`ipmann et al., 1947) indicated the vita- min's biochemical role and led to the demonstration that pantothenic acid-deficient rats had defects in the ability to metabolize fatty acids. NUTRITIONAL ROLE Dietary Requirements of Various Species Signs of pantothenic acid deficiency vary in different species (Sauberlich, 1980; Fox, 1984~. An effect on growth response usually can be demonstrated. Most pantothenic acid-deficient laboratory animals exhibit dermatitis, achromotrichia, and nasal porphyrin excre- tion. Pantothenic acid-deficient poultry exhibit a feath- ering disorder, fatty livers, and a characteristic dermatitis in the corners of the mouth. Deficiency signs are readily produced in most labora- tory animals. The dietary requirements for rats, mice, and guinea pigs are 8 to 20 mg/kg of diet; for chicks, 10 mg/kg; for swine, 13 mg/kg; and for dogs and cats, 10 mg/kg. No daily dietary requirements for pantothenic acid have been established for ruminants, horses, or humans. Estimates of human adult daily intakes of the vitamin in the United States range from 5 to 20 mg/day (Sauberlich, 1980~. 67 Biochemical Functions Pantothenic acid is a component of coenzyme A, acyl CoA synthetase, and acyl carrier protein. The coen- zyme form of the vitamin is therefore responsible for acyl group transfer reactions. The acyl derivatives of coenzyme A are activated thiol esters of the h-mercapto- ethylamine portion of the molecule, which is attached to the carboxyl group of pantothenic acid to form the ac- tive coenzyme. These activated acyl groups are in- volved in condensations, acyl group exchanges, and acyl group transfers catalyzed by a number of enzymes. Coenzyme A derivatives are also involved in fatty acid degradation, and fatty acids are synthesized as acyl car- rier protein derivatives. FORMS OF THE VITAMIN Pantothenic acid consists of pantoic acid ((x,~-dihy- droxy-$,h'-dimethylbutyric acid) joined to ,B-alanine by an amide bond (Figure 15~. Much of the pantothenic acid in tissues consists of the coenzyme forms of the vitamin. These forms all have ,B-mercaptoethylamine bound as an amide to pantothenic acid and have a 4'-phosphate joined to a 3',5'-adenosine diphosphate (ADP) by a pyro- phosphate in coenzyme A, or to a serine residue of acyl carrier protein or acyl CoA synthetase. This mixture of coenzymes is to a large extent acylated in tissues. Anal- yses of the vitamin in foods and tissues have most often been carried out by microbiological methods, and enzy- matic digestion has been used to liberate pantothenic acid from the various coenzyme forms. The form used in the supplementation of animal feeds is the salt, calcium pantothenate.
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6~3 Vitamin Tolerance of Animals ABSORPTION AND METABOLISM CH3 OH O 1 1 11 HO CH2 ---- C CH C N CH2 CH2 COOH 1 1 CH3 H Pantothenic acid SH H2 ~H2 NH C-O H2 ~H2 NH C=0 CHOH CH3-C CH3 l H2 o -O-P=0 o I NH2 -o P-0 1 O ~C ~ ON I HC Il I CH \N,C ~ ITCH HUH O OH PO3 Coenzyme A FIGURE 15 coenzyme A. ,B- Mercaptoethylamine Pantothenic acid 1 - Adenine Ribose 3 -phosphate Chemical structures of pantothenic acid and Pantothenic acid activity is widely distributed in feeds and foods, where it is present as a mixture of coenzyme forms. These forms of the vitamin are presumably hy- drolyzed in the intestine. Serum contains predomi- nantly free pantothenic acid. Cellular enzymes convert pantothenic acid to coenzyme A through a pathway that involves phosphorylation, addition of the h-mercapto- ethylamine group, and, finally, addition of the nucleo- tide. Excess pantothenic acid is excreted in the urine, and changes in dietary intake can be followed by urinary excretion (Fox, 19841. HYPERVITAMINOSIS Pantothenic acid is generally regarded as nontoxic (Omaye, 1984~. No adverse reactions have been re- ported in any species following the ingestion of elevated levels of pantothenic acid in the diet. Unna and Greslin (1941) determined an acute LD50 value for calcium pan- tothenate of about 1 g/kg of BW by parenteral injection for the rat but no toxicity at a dose of 10 g/kg of BW administered orally. They also reported that rats fed 200 mg of calcium pantothenate/day (about 20 g/kg of diet) for 190 days showed no adverse effects as far as growth nor any evidence of gross pathology. Wirtschafter and Walsh (1962) reported liver damage, as measured by lipid deposition and elevated serum glutamic/ oxaloacetate transaminase activities, following the in- tramuscular injection of 20 mg of sodium pantothenate (about 80 mg/kg of BW) to rats. The severity of the response increased when greater doses were adminis- tered. PRESUMED UPPER SAFE LEVELS No adverse responses to the ingestion of pantothenic acid have been documented. The upper limits of pre- sumed safe dietary levels cannot be established. It is clear, however, that dietary levels of at least 20 g of pantothenic acid/kg can be tolerated by most species. SUMMARY 1. Pantothenic acid can be administered orally or in the diet at an intake of 10 g/kg of BW with no adverse effects. 2. Parenterally administered pantothenic acid has an acute LD50 of about 1 g/kg of BW for the rat. Doses of about 80 mg/kg of BW have been shown to be associated
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Pantothenic Acic! 69 with nonfatal liver damage. This amount is approxi- mately 100 times the daily dietary requirement for the vitamin. REFERENCES Fox, H. M. 1984. Pantothenic acid. Pp. 437-458 in Handbook of Vitamins, L. J. Machlin, ed. New York: Marcel Dekker. Lipmann, F., N. O. Kaplan, G. D. Novelli, L. C. Tuttle, and B. M. Guirard.1947. Coenzyme for acetylation, a pantothenic acid deriva- tive. J. Biol. Chem. 167:869. Olson, R. E. 1984. Pantothenic acid. Pp. 377-382 in Present Knowl- edge in Nutrition, R. E. Olson, ed. Washington, D.C.: The Nutrition Foundation. Omaye, S. T. 1984. Safety of megavitamin therapy. Adv. Exp. Med. Biol. 177:169. Sauberlich, H. E. 1980. Pantothenic acid. Pp. 209-215 in Modern Nutrition in Health and Disease, R. S. Goodhart and M. E. Shils, eds. Philadelphia: Lea & Febiger. Unna, K., and J. S. Greslin.1941. Studies of the toxicity and pharma- cology of pantothenic acid. J. Pharmacol. Exp. Ther. 73:85. Williams, R. J.1939. Pantothenic acid-A vitamin. Science 89:486. Wirtschafter, Z. T., and J. R. Walsh. 1962. Hepatocellular lipid changes produced by pantothenic acid excess. Ann. Surg. 15:976.
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