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. 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 B12; and 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. Work with chicks and rats indicated that 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 cotransport 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.
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. 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
The most important function of CoA is to act as a carrier mechanism for carboxylic acids (Miller et al., 2006; Rucker and Bauerly, 2007). 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 the 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).
For growth and reproduction, the majority of animal species have a dietary requirement between 5 and 15 mg per kg (2.3 to 6.8 mg per lb) of diet. 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. 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). High fat levels may increase the pantothenic acid requirement (Sewell et al., 1962) of swine while high dietary protein has been suggested to decrease the requirement (Luecke et al., 1952). 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 in comparison with 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 coenzyme A for metabolism.
It has been suggested that antibiotics may have a sparing effect on the pantothenic acid requirement of animals. A dietary level of 22 mg per kg (10 mg per lb) Aureomycin (chlortetracycline) for weanling pigs (McKigney et al., 1957) and 10 mg per kg (4.5 mg per lb) of procaine penicillin for turkey poults (Slinger and Pepper, 1954) reduced the pantothenic acid requirement for these species. Certain amounts of B-complex vitamins (including pantothenic acid) are synthesized in the large intestine of animals. 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, those between pantothenic acid and vitamin B12, ascorbic acid and biotin (Scott et al., 1982). A five-fold increase in CoA content of liver was found in B12-deficient chicks and rats. Also, there have been suggestions of a possible interrelationship between folic acid and biotin with pantothenic acid. 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).
McKibbin et al. (1940) reported that puppies had a requirement of 100 µg calcium panthothenate per kg (45.5 µg per lb) body weight per day, with less needed for adults. Dogs died when fed a diet containing no pantothenic acid or a low supplemental level. At higher levels of pantothenic acid feeding, 200 to 1,000 µg per kg (91 to 455 µg per lb) of body weight, there was no difference in weight gains. However, dogs receiving the higher supplemental levels showed an earlier but transitory antibody response when exposed to distemper and infectious hepatitis (Sheffy, 1964). According toNRC (2006), the pantothenic acid requirement for all classes of dogs is 15 mg per kg (6.8 mg per lb) of diet. The Association of American Feed Control Officials (AAFCO, 1992) recommends 10 mg pantothenic acid per kg (4.5 mg per lb) of diet for all classes of dogs.
There is only one report on the pantothenic acid requirement of the cat (Gershoff and Gottlieb, 1964). Starting with three-month-old kittens, a semi-purified diet with six different levels of calcium pantothenate was fed for nearly two years. Based on weight gain, freedom from deficiency signs, and the efficiency with which p-amino-benzoic acid was acetylated, these workers concluded that 3 mg of calcium pantothenate per kg (1.40 mg per lb) of diet was inadequate, but 5 mg of calcium pantothenate per kg (2.3 mg per lb) of diet was sufficient. According to NRC (2006), the pantothenic acid requirement for kittens after weaning is 5.7 mg per kg (2.59 mg per lb) of diet and for all other classes of cats is 5.75 mg per kg (2.61 mg per lb) of diet and AAFCO (2007) suggest 5 mg of pantothenic acid per kg (2.3 mg per lb) of diet for cats.
“Pantothenic acid” is derived from the Greek word “pantos” meaning “found everywhere”. Although this vitamin is found in practically all foodstuffs, the quantity present is generally insufficient for most monogastric species. Pantothenic acid is widely distributed in feedstuffs of animal and plant origin. Alfalfa hay, peanut meal, cane molasses, yeast, rice bran, green leafy plants, wheat bran, brewer’s yeast, fish solubles and rice polishings are good sources of the vitamin for animals. Corn and soybean meal diets are apt to be low in pantothenic acid.
Many swine and poultry diets are borderline in supplying pantothenic acid requirements and many are deficient in this vitamin. However, pet foods that are rich in animal grain by-products should be adequate in the vitamin. Cat food compared to dog food could be higher in pantothenic acid. Milling by-products such as rice bran and wheat bran are good sources, being two to three times higher than the respective grains. Biological availability of pantothenic acid is high from corn and soybean meal, but low from barely, 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 me per lb) more recently (Palagina et al., 1990).
Pantothenic acid is reported to be fairly stable in feedstuffs during long periods of storage (Scott et al., 1982). The authors indicate that heating during processing may cause considerable losses, especially if temperatures attain 100°C 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 moisture. Pelleting was reported to cause only small losses of the vitamin. As a general guideline, pantothenic acid activity in normal pelleted feed over a period of three months at room temperature should be 80% to 100%. 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% (Song, 1990).
Higher concentrations of pantothenic acid are found in the rumen then found in the dietary components, indicating microbial synthesis of the vitamin. Pearson et al. (1953) found that the urinary and fecal excretion of pantothenic acid was four to six times the intake when semi-synthetic diets were fed. Pantothenic acid excretion increased with increased crude protein intake. For young ruminants, milk from the dam is a good source of the vitamin, with colostrum and whole milk from cows containing about 1.73 to 3.82 µg of pantothenic acid per ml, respectively (Foley and Otterby, 1978)
Pantothenic acid is available as a commercially synthesized product for addition to feed. It is available as d- or dl-calcium pantothenate. One gram of d-calcium pantothenate is equivalent to 0.92 grams of pantothenic acid activity, while the racemic mixture of 1 gram of the dl form has 0.46 gram of d-pantothenic acid activitiy. Because livestock and poultry can utilize, biologically, only the d isomer of pantothenic acid, nutrient requirements of the vitamin are routinely expressed as the d form.
On the basis of observations of pantothenic acid-deficient animals and studies in human volunteers, deficiency of the vitamin is shown in the following signs and symptoms:
Clinical signs of pantothenic acid deficiency take many forms and differ from one animal species to another. For humans, additional emotional and neurological symptoms include hyperventilation, irritability, insomnia, depression, headache, and dizziness. Pantothenic acid deficiency does occur under certain feeding regimens with animals.
Studies of pantothenic acid deficiency in various animal species indicate lowered tissue levels and decreased urinary excretion of the vitamin and decreased tissue coenzyme A (Nelson, 1978). Deficient dogs have reduced concentrations of pantothenic acid in blood, liver, muscle, and brain (Silber, 1944). Scudi and Hamlin (1942) found lowered blood levels of cholesterol, lipids, and lipid phosphorus in panthothenic acid-deficient puppies. However, present data are insufficient to establish pantothenic acid status for dogs and cats based on critical concentrations.
Fouts et al. (1940) reported clinical signs of pantothenic acid deficiency to result in decreased appetite and loss of body weight. Diarrhea occurred in all animals between seven and 66 days of the start of the experiment. Diarrhea became severe and bloody just prior to death. Vomiting was frequent. Animals became quiet and very weak prior to death.Schaeffer et al. (1942a) reported that vomiting was sometimes so severe in pantothenic acid-deficient dogs that feces occurred in the vomit. In the terminal stages of pantothenic acid deficiency, dogs exhibit spasticity of the hind quarters, sudden prostration or coma, usually accompanied by rapid respiratory and heart rates and possible convulsions (NRC, 2006). From the Fouts et al. (1940) study, skin ulcers were found over the shoulder, neck and back of the pantothenic acid-deficient dogs. There was alopecia and graying of some hair. Anemia was noted in six of seven dogs. Survival averaged 243 days, varying from 197 to 289 days. Fatty livers were noted along with ulcers in the mouth, ileum, and stomach (Ralston Purina, 1987). A pantothenic acid-deficient diet resulted in erratic food intakes of puppies within two to three weeks and adult dogs within seven to eight weeks (Sibler, 1944).
Gantt et al. (1959) demonstrated the effect of pantothenic acid deficiency on conditional reflexes. Noticeable loss of conditional reflex performance was found four to 10 days before any neurologic signs or blood alteration. This loss of conditional reflex was reversible with added pantothenic acid.
The terminal stages of acute pantothenic acid deficiency were observed after two to 4.5 months in kittens fed an unsupplemented semi-purified diet (Gershoff and Gottlieb, 1964). There was no alopecia or graying of hair. Livers and intestinal tracts were particularly affected. Growth failure and histological changes were the main signs of pantothenic acid deficiency. Livers had fatty metamorphosis, vacuolar formations, but no cirrhosis or increased fibrous tissue. Giant, blunted villi were seen in some areas of the jejunum and upper ileum with the tops of the villi in some animals necrotic.
Since most plant and animal feeds are good sources of pantothenic acid, deficiency of the vitamin should not ordinarily be any problem to dogs and cats. Cats in particular would not be expected to develop a pantothenic acid deficiency as their diets are usually higher in protein. High-protein diets would reduce pantothenic acid needs due to the decreased level of dietary carbohydrate, which would presumably require coenzyme A for metabolism. However, to be safe, pantothenic acid is usually added to nutritionally complete cat and dog foods since it costs so little. Even though dog and cat foods should be adequate in pantothenic acid, there are large variations in quantities and processing of foods that can further reduce the quantity present. Feed-grade pantothenic acid 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 a buyer who is not fully aware of the biological activity supplied by d-pantothenic acid. 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. Because it readily picks up moisture, it sticks to bags, cans, and scoops and can become hard after prolonged 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 and essentially non-hygroscopic and non-electrostatic products.
Pantothenic acid is reportedly fairly stable in feedstuffs during long periods of storage (Scott et al., 1982). The authors indicate 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. Loss of the vitamin in dairy products during processing and storage is about 30% to 35% (Song et al., 1990). 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 stored for a period of three months at room temperature should be 80% to 100% of the original value. Pantothenic acid stability in a vitamin premix was 98% after six months; however, when the premix contained choline and trace minerals, the quantity of the vitamin retained was only 58% (Gadient, 1986).
Pantothenic acid is generally regarded as nontoxic. No data have been reported for pantothenic acid toxicity studies with dogs or cats. Unna and Greslin (1941) determined an acute LD50 value for calcium pantothenate of about 1 g per kg (0.45 g per lb) of body weight by parenteral injection for the rat, but no toxicity at a dose of 10 g per kg (4.5 g per lb) administered orally. Dietary levels of at least 20 g pantothenic acid per kg (9.1 g per lb) can be tolerated by most species (NRC, 1987). In rats, 100 times the dietary requirement resulted in nonfatal liver damage (NRC, 1987).
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