Table

Protective Mechanisms against Oxygen Radicals*

Preventative Antioxidant

Mechanism

Vitamin C

Superoxide dismutase (SOD)

Glutathione (GSH) peroxidase

Peroxidase

Transferrin

Ceruloplasmin

Allopurinol

Chain-Breaking Antioxidant

Vitamin E Vitamin C Glutathione (GSH) Coenzyme Q

Scavenger Enzymatic Enzymatic Enzymatic Iron requiring Copper requiring Iron requiring

Mechanism

Terminates lipid peroxidation Terminates lipid peroxidation Regenerates vitamin E from its radical Regenerates vitamin E from its radical

*The systems that protect us against oxygen radicals may be categorized as preventable or chain breaking — vitamin C functions in both categories

The other system includes chain-breaking antioxidants, such as uric acid, ubiquinone, bilirubin, vitamin C, vitamin E, cysteine, and glutathione (GSH). These terminate the chain reaction of the lipid peroxidation reaction by scavenging oxygen-free radical reactions within and outside of the cell. It is thought that the decreased tissue concentration of vitamin C under invasive situations, such as burn injury, shock, and multiple trauma, is largely due to vitamin C consumption in these processes21 (Figure 8.6).

Because vitamin C is water soluble, it is an aqueous phase antioxidant. It may function as a preventive antioxidant by scavenging oxygen radicals, such as superoxide (O-), hydroxyl radical (OH-) and singlet oxygen (O2).22-24 Along with vitamin E, it also has a chain-breakage-type antioxidizing effect, terminating oxygen radical reaction within and outside of cell membranes.21 Vitamin C can interact with and remove the oxygen radicals from the vitamin E free radicals and, thus, regenerate vitamin E (Figure 8.6). Other reducing compounds, such as cysteine and glutathione, also reduce the vitamin E radicals but at a slower rate than that of vitamin C (Figure 8.7). One

radical

FIGURE 8.6 Interrelationship of vitamin E and vitamin C. Lipid-free radicals may be reduced by vitamin E. The vitamin E radical may subsequently be regenerated by vitamin C in the cell membrane (L = lipid).

radical

FIGURE 8.6 Interrelationship of vitamin E and vitamin C. Lipid-free radicals may be reduced by vitamin E. The vitamin E radical may subsequently be regenerated by vitamin C in the cell membrane (L = lipid).

FIGURE 8.7 Vitamin C and vitamin E interactions. Vitamin C can interact with and remove the oxygen radicals from the vitamin E free radicals and, thus, regenerate vitamin E (see also Figure 8.6). Other reducing compounds, such as cysteine and glutathione, and enzyme systems also reduce the vitamin E radicals but at a slower rate than that of vitamin C. (From Niki, E., Ann. N.Y. Acad. Sci, 498, 186, 1987. Reprinted by permission.)

FIGURE 8.7 Vitamin C and vitamin E interactions. Vitamin C can interact with and remove the oxygen radicals from the vitamin E free radicals and, thus, regenerate vitamin E (see also Figure 8.6). Other reducing compounds, such as cysteine and glutathione, and enzyme systems also reduce the vitamin E radicals but at a slower rate than that of vitamin C. (From Niki, E., Ann. N.Y. Acad. Sci, 498, 186, 1987. Reprinted by permission.)

may speculate that an adequate amount of ascorbate in the extracellular fluid continuously scavenges oxygen radicals that are spilled into the extracellular fluid. Thus, vitamin C protects both the capillary endothelium and the circulating cells, such as erythrocytes and leukocytes, from oxygen injury. As a result, it is thought to be the major plasma antioxidant in the human body.12526

Understanding how the free radical scavenging property of vitamin C may aid in wound healing requires a review of the basic process of wound healing and inference from a variety of clinical situations (Chapter 1). During the inflammatory stage of wound healing, and to a lesser degree throughout the healing process, inflammatory cells and other processes in the healing wound produce free radicals, presumably for their bacterial killing properties. Unfortunately, in some cases, this process may exceed its usefulness and cause local "collateral damage" to the host. In addition, in situations of metabolic stress, such as burns and trauma, systemic inflammatory response syndrome (SIRS) may ensue, leading to a systemic excess of oxygen free radicals. In this situation, the metabolic response to injury may initiate cascades of tissue and organ damage throughout the body (Chapter 11). Clearly, control of the inflammatory response in this situation may be life saving.27,28

ascorbic acid requirements

In addition to its function in collagen production, ascorbic acid enhances neutrophil function, increases angiogenesis, and functions as a powerful antioxidant.26 Thus, while most discussions of vitamin C and wound healing concentrate on its pivotal function in the accumulation and cross-linking of collagen, the other functions of ascorbate must not be ignored. To address the amount of ascorbate that must be included in the diet for wound healing, the function one is attempting to support must be considered, as the dietary requirements may be different for these different functions, as seen below.

Oral ascorbate is readily absorbed by the bowel by an energy requiring a Na+-dependent transport system.111 It passes through the portal circulation to circulate in the plasma unbound as ascorbic acid. Little or no other species are found in the blood.29 Circulating ascorbate is readily filtered through glomeruli and reabsorbed in the proximal collecting tubule.30 After saturation of these resorptive mechanisms, ascorbic acid is excreted in the urine. Regulation of concentrations of ascorbate in the body appears to be achieved at multiple levels, including a noninducible active absorption in the bowel and by saturatable renal absorption.11 27 31 This would indicate that although it is difficult if not impossible to develop progressively high tissue or plasma levels of ascorbate with oral intake in an individual with normal kidney function, these protective mechanisms would not be active in individuals receiving intravenous ascorbate or in a patient with renal failure (Figure 8.8).

In most tissues of the body, ascorbate is accumulated against a concentration gradient in millimolar concentrations. The concentration in human tissues varies from 5 to 15 mg/100 mg in the kidney to 30 to 50 mg/100 mg in the adrenal or pituitary gland.110 It is unclear why cells accumulate ascorbate, but this must be related to the metabolic function of tissues that need ascorbate as either cofactors for enzymatic reactions or as a mechanism to control harmful free radicals. In

FIGURE 8.8 Functioning doses of intracellular vitamin C in circulating cells. The concentration of intracellular vitamin C plateaus at relatively low levels of vitamin C intakes indicate that most of the higher doses are secreted in the urine. (From Levine, M., Katz, A., and Padayatty, S., in Modern Nutrition in Health and Disease, Lippincott Williams & Wilkins, Philidelphia, 2006, chap. 31, p. 517. With permission. From Levine, M., Wang, Y., Padayatty, S.J., et al., Proc. Natl. Acad. Sci. U.S.A., 98, 9842-9846, 2001, with permission of the National Academy of Sciences, Washington, D.C.)

FIGURE 8.8 Functioning doses of intracellular vitamin C in circulating cells. The concentration of intracellular vitamin C plateaus at relatively low levels of vitamin C intakes indicate that most of the higher doses are secreted in the urine. (From Levine, M., Katz, A., and Padayatty, S., in Modern Nutrition in Health and Disease, Lippincott Williams & Wilkins, Philidelphia, 2006, chap. 31, p. 517. With permission. From Levine, M., Wang, Y., Padayatty, S.J., et al., Proc. Natl. Acad. Sci. U.S.A., 98, 9842-9846, 2001, with permission of the National Academy of Sciences, Washington, D.C.)

addition, it is clear from this that assessments of vitamin C nutrition based on plasma levels alone may be erroneous, as plasma levels may not reflect tissue levels. Most investigators use concentrations of circulating cells as an acceptable index of ascorbate nutrition, but many studies still report plasma levels.1,11,27

Dietary reference intakes for ascorbate for the general population are found in Table 8.4. The results were based on neutrophil vitamin C concentrations, putative

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