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DSM in Animal Nutrition & Health

Pantothenic Acid

Properties and Metabolism

Pantothenic acid is found in two enzymes, coenzyme A (CoA) and acyl carrier protein (ACP), which are involved in many reactions in carbohydrate, fat and protein metabolism. The structural formula and crystalline structure are shown in Illus. 14-1. The free acid of the vitamin is a viscous, pale yellow oil readily soluble in water and ethyl acetate. It crystallizes as white needles from ethanol and is reasonably stable to light and air. The oil is extremely hygroscopic and easily destroyed by acids, bases and heat. Maximum heat stability occurs at pH 5.5 to 7.0. Calcium pantothenate is the pure form of the vitamin used in commerce. Pantothenic acid is optically active (characteristic of rotating a polarized light). It may be prepared either as the pure dextrorotatory (d) form or the racemic mixture (dl) form. The racemic form has approximately one-half the biological activity of d-calcium pantothenate. Only the dextrorotatory form, d-pantothenic acid, is effective as a vitamin.

 

Illustration 14-1

14Illustration_14-1_PanthothenicAcid

The most common antagonist of pantothenic acid is omega-methyl-pantothenic acid, which has been used to produce a deficiency of the vitamin in humans (Hodges et al., 1958). Other antivitamins include pantoyltaurine, phenylpantothenate hydroxycobalamine (c-lactam), an analog of vitamin B12and antimetabolites of the vitamin containing alkyl- or aryl-ureido and carbamate components in the amide part of the molecule (Fox, 1991; Brass, 1993). Pantothenic acid is found in feeds in both bound (largely as CoA) and free forms. It is necessary to liberate the pantothenic acid from the bound forms in the digestive process prior to absorption. Pantothenic acid, its salt, and the alcohol are absorbed primarily in the jejunum by a specific transport system that is saturable and sodium ion dependent (Fenstermacher and Rose, 1986). The alcohol form, panthenol, which is oxidized to pantothenic acid in vivo, appears to be absorbed somewhat faster than the acid form. After absorption, pantothenic acid is transported to various tissues in the plasma from which it is taken up by most cells via another active-transport process involving co-transport of pantothenate and sodium in a 1:1 ratio (Olson, 1990). Within tissues, pantothenic acid is converted to CoA and other compounds where the vitamin is a functional group (Sauberlich, 1985). Free pantothenate appears to be efficiently absorbed. In the dog, between 81% and 94% of an oral dose of sodium [14C] pantothenate was absorbed (Taylor et al., 1974). Measurement of pantothenic acid bioavailability in adult men consuming a typical United States diet ranged from 40% to 61%, with an average of 50% (Sauberlich, 1985). Urinary excretion is the major route of body loss of absorbed pantothenic acid, and excretion is prompt when the vitamin is consumed in excess. Most pantothenic acid is excreted as the free vitamin, but some species (e.g., dog) excrete it as beta-glucuronide (Taylor et al., 1972). An appreciable quantity of pantothenic acid (~15% of daily intake) is oxidized completely and is excreted across the lungs as CO2.

Livestock do not appear to have the ability to store appreciable amounts of pantothenic acid; organs such as the liver and kidneys have the highest concentrations. The majority of pantothenic acid in blood exists in red blood cells as CoA, but free pantothenic acid is also present.

 

Functions

Pantothenic acid is a constituent of two important coenzymes, CoA and ACP. Coenzyme A is found in all tissues and is one of the most important coenzymes for tissue metabolism (Miller et al., 2006; Rucker and Baverly, 2007). The coenzymes are known to be involved in more than 100 different metabolic pathways involving the metabolism of carbohydrates, proteins and lipids and the synthesis of lipids, neurotransmitters, steroid hormones, porphyrins and hemoglobin. The important role of CoA is summarized in Figure 14-1. 

 

Figure 14-1: The Important Role of Coenzyme A (CoA) in Metabolism

14Figure_14-1_The_Important_Role_of_Coenzyme_A

The most important function of CoA is to act as a carrier mechanism for carboxylic acids (Lehninger, 1982). Such acids, when bound to CoA, have a high potential for transfer to other groups, and such carboxylic acids are normally referred to as “active.” The most important of these reactions is the combination of CoA with acetate to form “active acetate” with a high-energy bond that renders acetate capable of further chemical interactions. The combination of CoA with two-carbon fragments from fats, carbohydrates and certain amino acids to form acetyl-CoA is an essential step in their complete metabolism because the coenzyme enables these fragments to enter the TCA cycle. For example, acetyl-CoA is utilized directly by combining with oxaloacetic acid to form citric acid, which enters the tricarboxylic acid (TCA) cycle. Coenzyme A, along with ACP, functions as a carrier of acyl groups in enzymatic reactions involved in synthesis of fatty acids, cholesterol and other sterols; oxidation of fatty acids, pyruvate and alpha-ketoglutarate; and biological acetylations. In the form of acetyl-CoA, acetic acid can also combine with choline to form acetylcholine, a chemical transmitter at the nerve synapse, and can be used for detoxification of various drugs, such as sulfonamides.

Decarboxylation of alpha-ketoglutaric acid in the TCA cycle yields succinic acid, which is then converted to the “active” form by linkage with CoA. Active succinate and glycine are together involved in the first step of heme biosynthesis. Pantothenic acid also stimulates synthesis of antibodies, which increase resistance of animals to pathogens. It appears that when pantothenic acid is deficient, the incorporation of amino acids into the blood albumin fraction is inhibited, which would explain why there is a reduction in the titer of antibodies (Axelrod, 1971).

 

Requirements

For growth and reproduction, the majority of animal species have a dietary requirement between 5 and 15 mg pantothenic acid per kg (2.3 to 6.8 mg per lb) of diet. Swine pantothenic acid requirements (NRC, 1998) range from 7.0 to 12.0 mg per kg (3.2 to 5.5 mg per lb) of diet. The highest requirement at 12 mg per kg (5.5 mg per lb) of diet is for young pigs and breeding animals. A low ambient temperature has been reported to increase the requirement (Blair and Newsome, 1985). Apparently there is a wide variation in pantothenic acid requirements among breeds and among animals within the same breed. In a study utilizing German Landrace pigs, Roth-Maier and Kirchgessner (1977) suggested an optimum requirement of 9 mg pantothenic acid per kg (4.1 mg per lb) of feed for market pigs based on growth, feed consumption and efficiency. In 1957, Barnhart et al. found no significant difference in rate of gain, daily feed consumed or feed:gain between weanling pigs fed varying levels of pantothenic acid ranging from 4.4 to 15.4 mg per kg (2 to 7 mg per lb) of a purified corn-soybean oil meal-based ration. The rations were fed from a body weight of approximately 11.4 to 45.5 kg (25 to 100 lb). Data from Michigan suggest that for one-half of growing pigs studied, 9.13 mg pantothenic acid per kg (4.2 mg per lb) of diet was sufficient for growth, whereas the remaining half required more than this but less than 13.5 mg per kg (6.1 mg per lb) (Luecke et al., 1953). After evaluating levels of 5, 7.5, 10, 12.5 and 15.0 mg of supplemental calcium pantothenate per kg (2.3, 3.4, 4.5, 5.7, and 6.8 mg per kg) of diet, Stothers et al. (1955) suggested a pantothenic acid requirement of 12.5 mg calcium pantothenate per kg (5.7 mg per lb) of dry matter in a synthetic milk for optimum growth and feed efficiency in baby pigs. High fat levels may increase the pantothenic acid requirement of swine (Sewell et al., 1962) while high dietary protein has been suggested to decrease the requirement (Luecke et al., 1952). Pigs fed a diet deficient in pantothenic acid and high in fat failed to gain weight, exhibited a lower feed efficiency and developed deficiency signs more quickly than those fed diets low in fat (Sewell et al., 1962). Nelson and Evans (1945) found that rats deficient in pantothenic acid fed a high-protein diet excreted more pantothenic acid and had accelerated growth and survival rates compared to rats fed a low-protein diet. The superiority of the high-protein diet may be due to the decreased level of dietary carbohydrate, which would presumably require CoA for metabolism. Pond et al. (1960) investigated the effect of dietary protein, fat and pantothenic acid on the performance of growing-finishing swine. In a 2x2x2 factorial experiment, pigs were fed dietary treatment combinations of high or low protein, high fat or no added fat, with different levels of pantothenic acid contained in the basal ration. Although less than the NRC recommendations were calculated to be present in the low-protein rations, level of pantothenic acid had no effect on any of the performance criteria measured.

It has been suggested that antibiotics may have a sparing effect on the pantothenic acid requirement of animals. A dietary level of 22 mg Aureomycin per kg (10 mg per lb) for weanling pigs (McKigney et al., 1957) and 10 mg procaine penicillin per kg (4.5 mg per lb) to turkey poults (Slinger and Pepper, 1954) reduced the pantothenic acid requirement for these species. Palm et al. (1968) fed young swine (weaned at three weeks) from three to nine weeks of age a conventional corn-soybean meal diet (18% protein) which was adequate in all vitamins but pantothenic acid. In addition, the diet contained 100 mg chlortetracycline, 110 mg sulfamethazone and 55 mg procaine penicillin per kg. The basal diet contained 4.26 to 8.09 mg of pantothenic acid per kg (1.94 to 3.67 mg per lb). No pantothenic acid deficiency signs were present, and rate and efficiency of gain were not improved by the supplementation of calcium pantothenate. These authors suggested that the minimum pantothenic acid requirement for young pigs is less than 13.2 mg per kg (6 mg per lb) of diet. Certain amounts of B complex vitamins (including pantothenic acid) are synthesized in the large intestine of swine. It is doubtful, however, whether much benefit is derived as only limited pantothenic acid absorption occurs in the large intestine, with the greatest benefit being in animals that practice coprophagy (Friesecke, 1975).

Interrelationships between other vitamins and pantothenic acid requirements are known. For example, the interrelationship of pantothenic acid and vitamin B12, ascorbic acid and biotin (Scott et al., 1982). A fivefold increase in CoA content of liver was found in vitamin B12-deficient chicks and rats. Also, there have been suggestions of a possible interrelationship between folic acid and biotin with pantothenate. Both vitamins were found necessary for pantothenic acid utilization in the rat (Wright and Welch, 1943). The inclusion of biotin in the diet of a pantothenic acid-deficient pig was effective in prolonging the life of the pig, but caused the pantothenic acid deficiency signs to appear in half the time (Colby et al., 1948).

 

Sources

Pantothenic acid is widely distributed in foods of animal and plant origin. Alfalfa hay, peanut meal, cane molasses, yeast, rice bran, green leafy plants, wheat bran, brewer’s years, fish solubles and rice polishings are good sources for animals. Many swine diets are borderline in supplying pantothenic acid and many are deficient in this vitamin. Corn and soybean meal diets are apt to be deficient in pantothenic acid. Milling by-products such as rice bran and wheat bran are good sources, having two to three times higher levels than the respective grains. Biological availability of pantothenic acid is high from corn and soybean meal, but low from barley, wheat and sorghum (Southern and Baker, 1981). Changing processing methods can greatly alter vitamin feed levels. As an example, with changes in sugar technology, literature values for pantothenic acid content of beet molasses have decreased from 50 to 100 mg per kg (22.7 to 45.5 mg per lb) in the 1950s, to about 1 to 4 mg per kg (0.45 to 1.8 mg per lb) more recently (Palagina et al., 1990). Compared to other small grains, barley is lower in pantothenic acid (Bowland and Owen, 1952). In their study, the barley-based ration provided about 5.9 mg of pantothenic acid per kg (2.7 mg per lb) of ration and resulted in similar performance with or without 3 to 12 mg of added pantothenic acid.

Pantothenic acid is reported to be fairly stable in feedstuffs during long periods of storage (Scott et al., 1982). The authors indicated that heating during processing may cause considerable losses, especially if temperatures are 100° to 150°C for long periods of time and pH values are above 7 or below 5. Gadient (1986) considers pantothenic acid to be slightly sensitive to heat, very sensitive to moisture and not very sensitive to oxygen or light. Pelleting was reported to cause only small losses of the vitamin. As a general guideline, pantothenic acid activity in pelleted feed over a period of three months at room temperature should be 80% to 100% original value. Pantothenic acid loss during processing of human foods is significant and can amount to as much as 70% in frozen meat and 80% in canned legumes. Loss of the vitamin in dairy products during processing and storage is about 30% to 35% (McDowell, 2000).

Pantothenic acid is available as a commercially synthesized product for addition to feed. It is available as d- or dl-calcium pantothenate. One g of d-calcium pantothenate is equivalent to 0.92 g of d-pantothenic acid activity. Because livestock and poultry can utilize, biologically, only the d isomer of pantothenic acid, nutrient requirements for the vitamin are routinely expressed as the d form.

 

Deficiency

Many swine diets are borderline in supplying pantothenic acid and many are deficient in the vitamin (Cunha, 1977). Early researchers documented a variety of the deficiency signs including those reported by Wiese et al. (1951) for baby pigs. Clinical signs of pantothenic acid deficiency take many forms and differ from one animal species to another. Non-specific signs of pantothenic acid deficiency in swine include reduced growth rate, bloody diarrhea, loss of appetite, poor general condition, lowered blood pantothenic acid and reduced feed conversion. Luecke et al. (1950) found that when a low-protein corn-soybean ration was supplied with thiamin, riboflavin, nicotinic acid and pyridoxine, signs of pantothenic acid deficiency were evident. Weanling pigs exhibited classical signs of pantothenic acid deficiency in this study when calcium pantothenate was excluded. These authors reported that the basal ration contained 9.3 mg of pantothenic acid per kg (4.2 mg per lb) of ration. The addition of supplemental pantothenic acid (22 mg calcium pantothenate per kg or 10 mg per lb of ration) without the other B-vitamins resulted in significantly greater gains than those of pigs fed the unsupplemented basal ration. A characteristic sign of a pantothenic acid deficiency in the pig is locomotor disorder (especially of hindquarters), which was described by Goodwin (1962). In the early stages of such a deficiency, the movement of back legs becomes stiff and jerky. Standing animals show a slight tremor of the hindquarters. When deficiency persists, this particular action of the rear legs grows more exaggerated and resembles the characteristic military gait, termed “goose stepping” (Illus. 14-2) (Luecke et al., 1953). The condition may be so severe that, as the pig moves forward, the back legs will touch the belly. Finally, an increasingly severe paralysis of the hindquarters develops. Affected pigs will frequently fall sideways or have their back legs spread apart in a posture resembling that of a sitting dog (Illus. 14-3). The chief microscopic lesion is chromatolysis of isolated cells of the dorsal root ganglia, followed by a demyelinating process in brachial and sciatic nerves.

 

Illustration 14-2: Pantothenic Acid Deficiency

14Illustration_14-2_Pantothenic_Acid_Deficiency

 

Illustration 14-3: Pantothenic Acid Deficiency

14Illustration_14-3_Pantothenic_Acid_Deficiency

McMillen et al. (1948) raised pigs on pasture beginning with an average body weight of 50.6 kg (111.3 lb) and supplied them with a corn-soybean meal ration plus casein, complex minerals, liberal amounts of A and D supplements, thiamin, riboflavin, niacin and pyridoxine. The pigs began “goose-stepping” in seven weeks. However, the control pigs which received 55 mg of pantothenic acid per kg (25 mg per lb) of feed remained normal. McMillen et al. (1948) observed a similar prevention of goose-stepping by pantothenic acid supplementation in dry-lot raised pigs. Such gait incoordination was observed in gilts provided with only 4.4 mg of supplemental pantothenic acid per kg (2 mg per lb) of ration (Davey and Stevenson, 1963). Pigs suffering from pantothenic acid deficiency have scaly skin and thin hair and a brownish secretion around the eyes. The dermatosis associated with deficiency appears principally on the shoulders and behind the ears; the skin appears dirty and scaly. Skin becomes reddened, and the bristles on the rump and along the spine loosen and fall. The dermatosis extends to the intestinal mucosa, where it becomes manifest as necrotic enteritis, ulceration and hemorrhages in the large intestine (Ullrey et al., 1955). As a consequence, the feces contain blood. Goodwin (1962) observed various degrees of gastritis and, occasionally, peritonitis and intestinal fissures.

Ullrey et al. (1955) observed pathologic changes in some of the other organs of sows and baby pigs maintained on pantothenic acid-deficient diets. These changes included fatty liver degeneration, enlarged adrenals and enlarged heart, with some related flaccidity of the myocardium and intramuscular hemorrhages. Histopathologic studies showed degenerative changes and necroses of the tissue cells. Stothers et al. (1955) observed a decrease in thickness of the glomerular layer of the adrenals in addition to many of the other symptoms of pantothenic acid deficiency reported by other researchers. Follis and Wintrobe (1945) compared the influence of pyridoxine or pantothenic acid deficiencies on nervous tissues of young pigs. These authors reported that while the most prominent and initial feature in pyridoxine deficiency was degeneration of the peripheral process of the sensory neurons, chromatolysis was the first evidence of damage to the afferent neuron in animals subjected to pantothenic acid deficiency.

Pantothenic acid is particularly important in sow fertility, with insufficient quantities of the vitamin resulting in complete reproductive failure (Ullrey et al., 1955). Estrus occurred but the sows failed to retain the embryos following breeding. Female hogs fed low-pantothenic acid diets developed fatty livers, enlarged adrenal glands, intramuscular hemorrhage, heart dilation, diminution of ovaries and improper uterine development (Ullrey et al., 1955). Davey and Stevenson (1963) reported in one of their trials that litter weights at weaning were reduced with lower pantothenic acid levels and appeared to be due to a reduction in litter size. The incidence of stillbirths was inversely related to dietary pantothenic acid levels. The data from their experiments suggested that reproductive performance and growth could be improved if pantothenic acid was increased from 4.4 mg to 11.9 mg per kg (2.0 to 5.4 mg per lb) of feed. Davey and Stevenson (1963) concluded that a minimum of 11.9 mg of pantothenic acid per kg (5.4 mg per lb) of diet is required in swine diets for maximum reproduction. Ensminger et al. (1951) reported that although gilts on a low-pantothenic acid diet became pregnant, they did not farrow or show any signs of pregnancy. Necropsy of gilts revealed macerating feti in the uterine horns in all cases. Minimal pantothenic acid sufficient to result in normal farrowing may still result in an abnormal locomotion in suckling pigs from sows that had received diets low in the vitamin (Teague et al., 1971). Sucking movements in the deficient piglets are impaired as is the use of the tongue (Christensen, 1983).

 

Fortification Considerations

Swine diets based on grains, particularly corn, are routinely supplemented with pantothenic acid. Field cases of pantothenic acid deficiency were frequently observed prior to the routine inclusion of supplemental pantothenic acid in swine diets made up chiefly of plant protein (Miller and Kornegay, 1983). Scott (1966) indicated that the pantothenic acid requirement for poultry may have to be increased 60% to 80% because of a lack of availability from bound forms in feeds. This would likely be true for swine. Southern and Baker (1981) estimated that the pantothenic acid present in both corn and dehulled soybean meal was 100% bioavailable. The bioavailability of pantothenic acid in barley, wheat and sorghum, however, was estimated to be only 60% based upon chick growth bioassay. Clinical pantothenic acid deficiency signs appear to be completely reversible, if not too far advanced, by oral treatment or injection with the vitamin followed by restoration of an adequate level of pantothenic acid in the diet. Type of diet influences the need for pantothenic acid supplementation. High-protein diets reduce pantothenic acid needs due to the decreased level of dietary carbohydrate, which presumably would require coenzyme A for metabolism. Pigs fed a pantothenic acid-deficient high-fat diet failed to gain weight, exhibited a lower feed efficiency ratio and developed deficiency signs more quickly than pigs fed diets low in fat (Sewell et al., 1962). Biotin and folic acid have been found necessary for pantothenic acid utilization, and vitamin B12 and antibiotics have a sparing effect for chicks (Latymer and Coates, 1981) and pigs (Latymer et al., 1985).

Because pantothenic acid has poor stability and poor handling properties, the calcium salt of pantothenic acid (calcium pantothenate) is the commercially available source of this vitamin for feed fortification. Calcium pantothenate shows good stability in feeds during manufacturing and storage. Feed-grade calcium pantothenate products are available in a number of potencies. Products that are sold on the basis of racemic mixture content can be misleading and confusing. To avoid confusion, the label should clearly state the grams of d-calcium pantothenate or its equivalent per unit weight and the grams of d-pantothenic acid.

A straight racemic mixture (90%) is available to the feed industry, but its hygroscopic and electrostatic properties contribute to handling problems. Readily picking up moisture, it sticks to packing materials and feed manufacturing and processing equipment, and it can become hard after long exposure to air. Its electrostatic properties cause it to cling to metallic and other objects, and losses can be significant. Through complexing procedures, several companies now market free-flowing, essentially non-hygroscopic and non-electrostatic products.

Verbeeck (1975) reported calcium pantothenate to be stable in premixes with or without minerals and regardless of the mineral form. Losses of calcium pantothenate may occur in premixes that are extremely acidic in nature, however. Use of a calcium pantothenate-calcium chloride complex instead of the plain calcium pantothenate should alleviate this problem.

 

Vitamin Safety

Pantothenic acid is generally regarded as non-toxic. No data have been reported for pantothenic acid toxicity studies with swine. Dietary levels of at least 20 gm pantothenic acid per kg (9.0 gm per lb) can be tolerated by most species (NRC, 1998). However, for poultry pantothenic acid became toxic at around 2,000 mg per kg (909 mg per lb) where reduced growth rate associated with liver damage was seen (Leeson and Summers, 2001).