Pantothenic acid and wound healing

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In a number of animal studies, oral pantothenic acid or topically applied panthenol was shown to accelerate the closure of skin wounds.28-31 Most of the mechanistic research done in this area involves looking at the impact pantothenic acid has on fibroblast function and concomitant wound closure and scar formation. Substantial amounts of work have also focused on how pantothenic acid enhances both collagen synthesis and collagen cross-linking and the role this vitamin plays in altering trace elements that have an impact on wound healing.

Because fibroblasts play such an important role in collagen formation, pan-tothenic acid has also been studied in regard to its effect on fibroblast migration, proliferation, and protein synthesis.32 In a fibroblast culture study conducted by Weimann and Hermann,33 it was observed that human dermal fibroblast migration into a wounded area was dose-dependently stimulated by calcium (Ca) D-pantothenate. The number of fibroblasts that migrated across the edge of the wound in their study when Ca D-pantothenate was not present was 32 ± 7 cells/mm. When 100 mg/ml of Ca D-pantothenate was present in the medium, this increased to 76 ± 2 cells/mm. Moreover, the mean migration distance/cell increased from 0.23 ± 0.05 mm to 0.33 ± 0.02 mm. The mean fibroblast migration speed increased from 10.5 mm/h when there was no Ca D-pantothenate to 15 mm/h when it was present. It was concluded in this study that Ca D-pantothenate accelerated the wound healing process by increasing the number of migrating cells, their distance, and their speed. Cell division and protein synthesis both were increased with the addition of Ca D-pantothenate to the culture.

In a study by Lacroix et al.,34 pantothenic acid's impact on protein metabolism in foreskin fibroblast cultures was determined. In these cultures, the addition of pantothenic acid led to a significant increase in cell proliferation and in 3H-thymidine incorporation. It was also noted that pantothenic acid stimulated intracellular protein synthesis but did not induce a release of proteins into the culture medium. In a separate but similar study,32 it was shown that pantothenic acid increased the basal incorporation of 14C-proline into precipitated material, and that the release of intra-cellular protein into the medium increased. The authors concluded that pantothenic acid might be of use in postsurgical therapy and wound healing for improvement of fibroblast activity as it is related to protein metabolism.

Studies have also been done with subjects who have had tattoos removed to determine the impact pantothenic acid has on the actual strength of scar tissue.35 In this study, 18 of 49 patients were supplemented for 21 d with both pantothenic acid (0.2 g/d) and vitamin C (1.0 g/d) prior to the removal of tattoos by successive resection. Hydroxyproline and trace element concentrations were measured in both skin and scar tissue. Fibroblast counts and mechanical properties of the scar tissue were also established. In the patients who received supplements, it was shown that the concentration of iron (Fe) in the skin increased, whereas manganese decreased; in scar tissue, Fe, copper (Cu), and manganese (Mn) decreased, and magnesium (Mg) increased. This type of mineral analysis is considered to be of importance, because ferrous Fe "overload" has been shown to have a negative effect on the wound healing process and to cause an increase in toxic hydroxyl radicals at the site of injury,36 with the concomitant development of a "poor" scar, whereas supplemental Cu improves collagen synthesis and seems to be involved in the cross-linking of collagen molecules.37 More specifically, lysyl oxidase has been shown to be involved in the cross-linking of collagen and elastin and requires a carbonyl cofactor in addition to Cu.17,38,39 It was also suggested that pyridoxal may act as the carbonyl cofactor. Cu was also shown to increase the activity of radical scavenging enzymes.40 Zinc (Zn) was shown to be a cofactor for more than 200 metalloenzymes that are involved in cellular growth as well as protein and collagen synthesis. When riboflavin is supplemented, Zn increases in scars, leading to a decrease in bacterial growth and an improvement in the inflammatory process of skin wound healing. In the present study, mechanical properties of scars in group A were correlated to the status of Fe, Cu, and Zn, with Zn and Cu both shown to be increased at the wound site. The authors proposed that this was of benefit, because both trace elements are known to improve collagen cross-linking41,42 as well as increase the activity of free radical scavenging enzymes.40 It was proposed that Fe might impair wound healing by catalyzing the production of toxic radicals.36 Results of this study suggested that benefits associated with ascorbic acid and pantothenic acid supplementation could be due to the variations in the trace element concentrations, as they are associated with the immunological response as well as the mechanical properties of scars.

Another study that focused on the mechanical properties of scars was done by Aprahamian et al.41 In this study, rabbits were provided with pantothenic acid supplements prior to having two colonic segments removed and then having continuity restored. Control animals received placebos prior to surgery. On the third postoperative day, the animals were killed, and the anastomoses were removed. Mechanical properties of both normal colon and anastomoses were determined using bursting pressure tests and tabulating the number of burst anastomoses. Other tests performed included fibroblast counts, hydroxyproline concentrations, and trace element content microanalysis for Mg, P, sulfur (S), sodium (Na), Fe, Cu, Zn, and manganese (Mn). Pantothenic acid decreased the number of burst anastomoses and restored normal Zn levels at the anastomotic site. Pantothenic acid supplementation also increased Fe, Cu, and Mn concentrations, all of which are intimately involved in collagen formation. It was clear that pantothenic acid enhanced colonic wound healing.

pyridoxine (vitamin b6)

Vitamin B6 plays a critical role in protein metabolism and occurs in three forms in the body as pyridoxine, pyridoxal, and pyridoxamine. All three forms of vitamin B6 are relatively stable in an acidic medium but are not heat stable under alkaline conditions. The active coenzyme forms are pyridoxal 5'-phosphate (PLP) and pyri-doxamine-5'-phosphate (PMP) (see Figure 7.6).

All forms of vitamin B6 are absorbed in the upper part of the small intestine. They are phosphorylated within the mucosal cells to form PLP and PMP. PLP can be oxidized further to form other metabolites that are excreted in the urine. Vitamin B6 is stored in muscle tissues.

PLP plays an important role in amino acid metabolism. It has the ability to transfer amino groups from compounds by removing an amino acid from one component and adding to another. This allows the body to synthesize nonessential amino acids when amino groups become available. The ability of PLP to add and remove amino groups makes it invaluable for protein and urea metabolism. Vitamin B6 is transferred in the blood both in plasma and in red blood cells. PLP and PMP can both be bound to albumin, with PLP binding more tightly, or to hemoglobin in the red blood cell. The liver is the primary organ responsible for the metabolism of vitamin B6 metabolites. As a result, the liver supplies the active form of PLP to the blood as well as to other tissues. The three nonphosphorylated forms of vitamin B6 are converted to their respective phosphorylated forms by pyridoxine kinase, with Zn and ATP as cofactors. PMP and pyridoxine can then be converted to PLP by flavin mononucleotide (FMN) oxidase.

It was shown in both animal and human studies that a low intake of vitamin B6 causes impaired immune function due to decreased interleukin-2 production and lymphocyte proliferation. It was also demonstrated that PLP inhibits the binding of steroid receptors to DNA and may, therefore, impact on endocrine-mediated diseases. It was suggested that reactions between physiologic concentrations of PLP and receptors for estrogen, androgen, progesterone, and glucocorticoids depend on the vitamin B6 status of an individual.

A number of vitamin B6 antagonists have been identified, including certain food additives, oral contraceptives, and alcohol.43 When alcohol is broken down in the body, acetaldehyde is produced, and acetaldehyde knocks PLP loose from its enzyme, which is broken down and then excreted. Thus, alcohol abuse causes a loss of vitamin B6 from the body. Some drugs have been shown to be vitamin B6 antagonists, including cycloserine, ethionarnide, furfural, hydralazine, isoniazid,

FIGURE 7.6 Vitamin B6 (pyridoxine).

isonicotinic acid, L-dopa, penicillamin, pyrazinamide, theophylline, and thiosemi-carbizones.44 Another drug that acts as a vitamin B6 antagonist is INH (isonicotinic acid hydrazide), a potent inhibitor of the growth of the tuberculosis bacterium. INH binds and inactivates the vitamin, inducing a vitamin B6 deficiency. In a number of disease states, it has been shown that apparent alterations of vitamin B6 metabolism can cause concomitant alterations in tryptophan metabolism. These alterations have been observed in patients with asthma, diabetes, breast and bladder cancers, renal disease, coronary heart disease, and sickle cell anemia.

High-protein diets have been shown to alter vitamin B6 requirements, because vitamin B6 coenzymes play important roles in amino acid metabolism. The RDA for vitamin B6 is 1.3 mg/d for adolescent and adult males up to the age of 50 and 1.7 mg/d for those age 51 and older. For women, the requirements are 1.2 mg/d for adolescents, 1.3 mg/d for adults until they reach the age of 50, and 1.5 mg/d for those who are age 51 yr and older.8 When vitamin B6 is deficient in the diet, symptoms include weakness, irritability, and insomnia. Advanced symptoms include growth failure, impaired motor function, and convulsions.

Vitamin B6 toxicity can arise if one routinely takes large doses of it over a lengthy period of time. This process may cause irreversible sensory neuropathy and nerve damage. Intakes of 200 mg/d or less show no evidence of damage; however, levels of 500 to 1000 mg/d have been associated with sensory damage.45

Excellent food sources include fortified cereal, baked potatoes (with skin), meats, fish, poultry, and green vegetables. The RDA for vitamin B6 in adolescent and adult males under the age of 50 yr is 1.3 mg/d, whereas for older adults, it is 1.7 mg/d. The RDA for females is 1.2, 1.3, and 1.5 mg/d, respectively, for adolescents, adults under the age of 51 yr, and adults over the age of 51 yr.8

vitamin b6 and wound healing

Vitamin B6 has been studied in regards to its role in inflammatory response. In rat studies by Lakshmi et al.,12 it was reported that pyridoxine deficiency led to increases in thiobarbituric acid reactive substance levels (30% and 43%, respectively) in the edematous paw and wounded skin. This is significant, because thiobarbituric acid concentrations are good indicators of lipid peroxidation. It was concluded that inflammation is enhanced when these animals are pyridoxine deficient.

It was also shown that vitamin B6 deficiency causes marked diminution in the glucose 6-phosphate dehydrogenase (G6PD) activity in the periosteal region of bone formation and in the developing callous. This causes a significant delay in the maturation of the callus. Deficiencies also caused changes in the bones that are suggestive of imbalance in the coupling between osteoblasts and osteoclasts. These results suggest that vitamin B6 status is important in the healing of fractures of bones.

folacin (vitamin b9)

Folic acid, or folate, consists of a pteridine base that is attached to one molecule each of P-aminobenzoic acid (PABA) and glutamic acid. Folacin is the generic term used for folic acid and related substances that act like folic acid. The structure is shown in Figure 7.7.

FIGURE 7.7 Vitamin B9 (folacin).

Folic acid has been shown to be involved in the transfer of one-carbon units, as well as in the metabolism of both nucleic acids and amino acids. Because of this, symptoms of deficiencies include anemia as well as an increase in serum homocys-teine concentrations.

Folate derivatives in the diet are cleaved by specific intestinal enzymes to prepare monoglutamyl folate (MGF) for absorption. Most MGF is reduced to tetrahydro-folate (THF) in the intestinal cells by the enzyme folate reductase. This enzyme uses NADPH as a donor of reducing equivalents. Tetrahydrofolate polyglutamates are the functional coenzymes in tissues. The folate coenzymes participate in reactions by carrying one-carbon compounds from one molecule to another. Thus, glycine can be converted to a three-carbon amino acid, serine, with the help of folate coenzymes. This action helps convert vitamin B12 to one of its active coenzyme forms and helps synthesize the DNA required for all rapidly growing cells. Enzymes on the intestinal cell surface, while hydrolyzing polyglutamate to monoglutamate, attach a methyl group. Special transport systems then help to deliver monoglutamate to the liver and other body cells. Folate is only stored in polyglutamate forms. When the need arises, it is converted back to monoglutamate and released. Excess folate is disposed of by the liver into bile fluid and stored in the gallbladder until it is released into the small intestine. An important role served by methyl THF is the methylation of homocysteine to methionine. Methylcobalamin serves as a cofactor along with vitamin B12. If these vitamins are missing, folate becomes trapped inside cells in its methyl form, unavailable to support DNA synthesis and cell growth.

Because folate is repeatedly reabsorbed, any injury to gastrointestinal tract cells causes an interference with absorption, and folate is lost from the body. The cells lining the gastrointestinal tract are the most rapidly renewed cells in the body, so not only will the folate be lost, but also other nutrients will not be absorbed.

Folate deficiency impairs both cell division and protein synthesis. Deficiencies of this vitamin are found most often in older people whose primary symptom is megaloblastic anemia. Another symptom is an increase in homocysteine concentrations. Deficiencies can also occur in patients who have cancer, skin-destroying diseases, and severe burns. Of all the vitamins, folate is most vulnerable to interactions with drugs, because some drugs have chemical structures similar to the vitamin.

High intake of folate from foods has not been shown to have negative side effects. The Food and Nutrition Board of the Institute of Medicine recommends that adults limit their intake of vitamin B12 to 1 mg/d in the treatment of megaloblastic anemia, and take care to ensure that the vitamin B12 deficiency does not mask a folate deficiency.8 This is critical, because misdiagnosis can result in irreversible neurological damage.

The RDA for folate in dietary folate equivalents (DFEs) is 400 mcg/d in both male and female adolescents and adults.8 Because animals cannot synthesize PABA or attach glutamic acid to pteroic acid, folate must be obtained from the diet. Common sources of folate are green leafy vegetables, fortified breakfast cereal, orange juice, and cooked pasta and rice.8

No adverse effects have been associated with excessive intake of folate from food sources.

folic acid and wound healing

Although specific studies have not been done in which folate needs are established in wound healing, the fact that this vitamin is required for the synthesis of DNA and for the methylation of DNA, as well as the metabolism of a number of important amino acids that are involved in the homocysteine/methionine pathway make it a critical vitamin for both before and after wound healing.

vitamin b12 (cobalamin)

Vitamin B12 (cobalamin; see Figure 7.8) is synthesized exclusively by microorganisms. Although vitamin B12 is absent from plants, it is synthesized by bacteria and is stored by the liver in animals as methyl cobalamin, adenosyl cobalamin, and hydroxyl cobalamin. Intrinsic factor (a highly specific glycoprotein in gastric secretions) is necessary for absorption of vitamin B12. After absorption, the vitamin is bound by a plasma protein (transcobalamin II) that transports it to various tissues. It is also stored in the liver in this form. The active coenzyme forms of vitamin B12 are methyl cobalamin and deoxyadenosyl cobalamin. In the blood, free cobalamin is released into the cytosol of cells as hydroxycobalamin. It is then either converted in the cytosol to methyl cobalamin or it enters mitochondria where it is converted to 5-deoxyadenosyl cobalamin. The methyl group bound to cobalamin is eventually transferred to homocysteine to form methionine, and the remaining cobalamin then removes the methyl group from N5-methyl tetrahydrofolate to form tetrahydrofolate (THF). Thus, in this metabolic process, methionine is stored, and THF is available to participate in purine, pyrimidine, and nucleic acid synthesis.46

A deficiency of vitamin B12 leads to the development of megaloblastic anemia. This deficiency can be caused by pernicious anemia, a condition in which an autoimmune inflammation occurs in the stomach that leads to a breakdown in the cells lining the stomach. Because the final result is a decrease in acid production, vitamin B12 cannot be released from food. Treatment of pernicious anemia requires vitamin B12 injections or high-dose supplementation. Approximately 2% of all adults over 60 yr of age have pernicious anemia.7 True vegetarians are at risk of vitamin B12 deficiency, because this vitamin is found only in foods of animal origin.

,CH3CH,/CH2C-NH, nh2c-ch2

O CH

NH2-C-CH

ch2ch2cnh2

CH3 CH

HN-C-CH2CH2CH3

nh2c-ch2

O CH

NH2-C-CH

HN-C-CH2CH2CH3

ch3Ch

O'Pb

HO N

HOCH2 O

ch2ch2cnh2

CH3 CH

FIGURE 7.8 Vitamin B12 (cobalamin).

A deficiency of this vitamin causes impairment in the methionine synthase reaction. Anemia is the result of impaired DNA synthesis, thus preventing cell division and formation of the nucleus of new erythrocytes, with consequent accumulation in the bone marrow of megaloblastic red blood cells.

A number of drugs have been shown to decrease absorption, including gastric acid inhibitors (Tagamet [GlaxoSmithKline], Pepcid [Merck and Co., Inc.], and Zantac [Warner Lambert Co.]) and proton pump inhibitors (omeprazole and lanso-prazole).47 Other drugs that inhibit absorption of vitamin B12 include cholestyramine (cholesterol binding agent), neomycin (antibiotic), and colchicine (gout treatment). A drug used in the treatment of adult onset diabetes (Metformin [Mylan Laboratories]) requires use with calcium-containing foods in order to allow for vitamin B12 absorption.48

The RDA for vitamin B12 is 2.4 mcg/d for adolescent and adult males and females.8 Food sources are found only in animal products such as cooked beef, salmon, and milk.

No toxic effects have been associated with intake of vitamin B12.

vitamin b12 and wound healing

Although specific studies have not been done that illustrate a direct relationship between vitamin B12 and wound healing, it is clear that its fundamental roles in the maintenance of red blood cells make it an important component of nutrition support before and after the wound was sustained.

b-vitamin intake

It is critical that B vitamins be included in the diet in adequate amounts as specified by the RDA or AI. B vitamins work in concert with each other, for example, if vitamin B12 deficiency is suspected, folate status should also be checked. People who are especially at risk of B-vitamin deficiency are those who have a history of alcoholism or those who have had a nutrient-deficient diet, such as older people or those who are poor or malnourished due to disease or malabsorption. If deficiencies are found, these should be corrected with supplemental B vitamins either individually or as a multiple vitamin.

When an oral diet is inadequate, B vitamins can be provided as a supplement in a multivitamin form that can be swallowed, or it can be provided in a liquid form. Most commercially available enteral (tube feeding) formulas have adequate amounts of B vitamins at a minimal level of formula intake. Higher levels of formula based on increased caloric needs should not pose a problem with toxicity for B vitamins.49,50 Patients who receive parenteral nutrition as their sole source or major source of nutrition support should be receiving an intravenous multivitamin product with adequate amounts of B vitamins. Individual B vitamins are also available in various forms to accommodate the absorptive capacity of the patient with wounds. If a nutrient deficiency is suspected and confirmed, supplementation will be necessary to bring the level to within normal limits.

Wound healing is dependent on B vitamins in a variety of ways. Both laboratory and clinical research indicate that the B vitamins are involved in all three phases of wound development. Studies have shown that B vitamins play a part in necrotic resorption, immunological response to infection, and the actual repair of wounds. These data also show that specific aspects of the recovery process are improved, such as fibroblast function and collagen synthesis and cross-linking. B vitamins should be provided in amounts that meet the RDA or AI and supplemented when deficient in order to assure that their functions in wound healing can be accomplished.

future directions for research

B vitamins have been treated as the neglected stepchild in the field of "nutrition and wound healing." It is clear that this family of vitamins plays a monumental role in wound healing in both the tissue repair process and in the optimization of immune function. Unfortunately, some of these vitamins (niacin, biotin, folacin, and vitamin B12) have not been individually studied in regard to their specific roles in the healing process. In general, more work needs to be done to establish specific roles for the B vitamins in wound healing and to determine how they interact with each other to allow for a successful outcome in the healing process.

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