Vitamin A is involved in numerous biochemical functions. The best-known action of vitamin A is in its function in the chemistry of vision. The requirement for vitamin A for proper visual response to light in the retina has been well characterized. However, its role in cellular growth and differentiation continues to expand.

The molecular mechanism of action of vitamin A, in the form of 11-cis retinal, in the visual process has been under investigation for many years.34,35 Figure 28.4 represents the

Rod Photoreceptor Retinal Pigmented Epithelial Cell

Rod Photoreceptor Retinal Pigmented Epithelial Cell

Figure 28.4 • Retinol and the visual cycle.

chemical changes that take place in the visual cycle involving the rhodopsin system in the rod cells of the retina. Uptake of retinol from blood by the epithelial cells of the retina is followed by re-esterification and conversion to the 11-cis retinol form. This is converted to the aldehyde, 11-cis retinal, which is the form used in the visual pathway. In contrast to the cone cells of the retina, which are responsible for color vision and only function well in the presence of ample light, the vitamin A-dependent rods are essential for vision over a wide range of light intensity, especially low levels. This system is responsible for vision in the dark, which explains the night blindness seen in vitamin A-deficient individuals.

Vitamin A is also intimately involved in cellular differentiation during embryonic development and the maintenance of cellular differentiation in various tissues in the adult. The molecular mechanism of vitamin A, in the form of retinoic acid, in this area is more complex.36,37 This form of vitamin A acts through retinoic acid receptors (RARs) which are a member of the steroid/thyroid hormone superfamily of receptors. These act as ligand-dependent transcription factors that regulate gene expression. Several RARs have been identified: RARa (RARA), RARS (RARB), and RARy (RARG). These differ in their tissue distribution and the level of expression during cell development and differentiation. Following cyto-plasmic RAR-retinoic acid binding, the complex forms a het-erodimer with the retinoid X receptor (RXR). The het-erodimer translocates to the nucleus and binds to a RARE or retinoid X response element (RXRE) on DNA associated with the promoter region of target genes and, together with coacti-vators, regulates target gene transcription. Several RXR receptors have also been identified including RXRa (RXRA), RXRS (RXRB), and RXRy (RXRG), and they have been shown to be also involved in the intracellular action of vitamin D. They have a different tissue distribution from the RARs. A specific ligand for RXR has been identified as 9-cis-retinoic acid, which can also bind to RARs; however, the physiological role of this retinoid is not known. Retinoic acid can bind only to RARs. 9-cis retinoic acid may, therefore, represent a third active form of vitamin A.38,39 Several synthetic retinoids have been synthesized that bind selectively to RXR receptors, and these are referred to as rexinoids.

The biological effects of retinoic acid are mediated through various proteins, numbering in the hundreds, which are controlled at the nuclear level by this form of the vitamin. Ultimately, effects are seen in cell differentiation, both during embryonic development and in the adult. Effects on reproduction, growth, immune function, hematopoiesis, epithelium, central nervous system (CNS) function, and cancer have also been observed, among others. This widespread involvement in biological function explains the myriad of effects seen in deficiency and overdoses of this vitamin.

Deficiency of this vitamin leads to several disorders collectively referred to as vitamin A deficiency disorders (VADD). Preschool-age children are especially susceptible to and develop more serious forms of VADD leading to increased mortality which may approach 50% in poor soci-eties.40 A deficiency of vitamin A is manifested chiefly by keratinization of the mucous membranes throughout the body. This degeneration is more pronounced in the eye than in any other part of the body and gives rise to a condition known as xerophthalmia which results in drying and thickening of the conjunctiva and cornea. This may ultimately lead to corneal destruction and permanent blindness.

Vitamin A deficiency also results in poor dark adaptation of the eyes referred to as night blindness (nyctalopia). Immune insufficiency develops resulting in a tendency to infection. Anemia results from hematopoietic failure in the marrow. In children, growth failure and wasting also occurs. Deficiency of vitamin A can also give rise to dryness and scaliness of the skin in adults.

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