Dna

Lipid hydroperoxidase Ascorbyl radical targets

Action

Regulate gene expression and mRNA translation, prevent oxidant to intracellular proteins

Quench aqueous peroxyl radicals and lipid peroxidation products

Prevent formation of N-nitroso compounds Pro-Oxidant

Effect

DNA damage

Decomposition of lipid peroxidase leading to DNA damage Cell damage

Source: From Levine, M., Katz, A., and Padayatty, S., in Modern Nutrition in Health and Disease, Shils, Shike, Ross, Caballero, and Cousins, Eds., Lippincott Williams & Wilkins, Philadelphia, 2006, chap. 31, p. 511. Adapted from Padayatty, S.J., Daruwala, R., Wang, Y. et al., in Handbook of Antioxidants, 2nd ed., Marcel Dekker, New York, 2002, pp. 117-145. With permission.

tyrosine metabolism also play a role.14,15 Deficiency of ascorbate and the effects on hormone and neurotransmitter production could also play a less obvious role, as it may have an effect on the ability of the organism to respond to the metabolic stress of injury.

Ascorbic acid is necessary for the posttranslational hydroxylation of proline and lysine residues in procollagen, which is necessary for its release from the ribosome and subsequent conversion to collagen13 (see also Chapter 1 and Chapter 4) (Figure 8.2). In the course of this reaction, ascorbic acid is reversibly oxidized to dehydroascorbic acid (DHASA). Hydroxyproline stabilizes the collagen triple-helix structure by hydrogen bonding. Hydroxylysine is essential for mature collagen cross-links that provide progressive tensile strength in the healing wound as well as in other tissues, such as skin, tendon, bone, vessel walls, and ligaments. Collagen types I and III are the major proteins of the healing wound and provide the majority of the tensile strength of that wound once healed. However, in addition to types I and III, there are numerous other collagen types, such as type IV collagen found in basement membrane and type II found in cartilage.16 Collagen also has an essential function in the extracellular matrix of all organs of the body as well as in the healing of all wounds invading below the epidermis. All of these collagen types require the same hydroxylation reactions for normal structure and function. Were this not enough, ascorbate is also

FIGURE 8.2 Posttransitional hydroxylation of procollagen. Inadequately hydroxylated procollagen will either be slowly secreted from the cell or intracellularly degraded, emphasizing the importance of the cofactors for the hydroxylation reaction. (PH, LH: prolyl and lysyl hydroxylases.) (Peterkofshy, B., Ascorbate requirements for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy, Am. J. Clin. Nutr., 54, 11365, 1991. With permission.)

FIGURE 8.2 Posttransitional hydroxylation of procollagen. Inadequately hydroxylated procollagen will either be slowly secreted from the cell or intracellularly degraded, emphasizing the importance of the cofactors for the hydroxylation reaction. (PH, LH: prolyl and lysyl hydroxylases.) (Peterkofshy, B., Ascorbate requirements for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy, Am. J. Clin. Nutr., 54, 11365, 1991. With permission.)

necessary in the hydroxylation reactions of other molecules with collagenous domains such as elastin and complement.17 It is not surprising that deficiency of collagen caused by ascorbate deficiency may have diffuse and severe manifestations.

Ascorbic acid deficiency causes abnormal collagen fibers and alterations of the extracellular matrix that manifest as cutaneous lesions, poor adhesion of endothelium cells, and decreased tensile strength of fibrous connective tissues, accounting for many of the manifestations in Table 8.1. It also explains the early descriptions of scurvy in sailors that included the breakdown of previously healed wounds. Clearly, ascorbate is not only essential for strong closure of the healing wound but also to maintain that closure for the rest of the life of the injured organism during the normal process of protein turnover (see also Chapter 4).

Vitamin c as a Free Radical Scavenger

Because the human body has adopted as its basic energy production the highly effective aerobic metabolic pathways, it constantly exposes itself to the "toxin" called oxygen. All nutrients may, in some cases, be harmful to the human body, especially when in excess quantities. While oxygen is essential for our survival, it also may be harmful to the body when in the form of free radicals. An oxygen radical is defined as an oxygen molecule with an unpaired electron in its outer orbital. Generally, these radicals are thought to provide an on-site defense system. On the other hand, it is also known that these same free radicals may attack the body (Figure 8.3).

The major pathway of oxygen metabolism occurring in man involves the tetravalent reduction of molecular oxygen by the cytochrome oxidase system in the mitochondria. However, 1 to 2% of the oxygen substrate may "leak" from the system to become metabolized by univalent reduction, producing various oxygen radicals.18 In addition, oxygen radicals can be produced by radiation, chemical agents, and various enzymatic systems, including xanthine oxidase and NADPH oxidase19,20 (Figure 8.3 and Figure 8.4).

Cause Oxygen radicals Effects

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