Tissue differentiation, retinoic acid

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

Retinoic Acid Has a Role in the Regulation of Gene Expression Tissue Differentiation... 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Vitamin A is essential for growth and development of cells and tissues. In its active form, retinoic acid (RA), it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations (Biesalski, 1996 Biesalski et al, 1999). Vitamin A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin A deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin A supplementation (Biesalski et ah, 2001 Greenberg et ah, 1997 John et ah, 1997). 

Vitamin A is essential for proper functioning of the retina, for the integrity of epithelial tissue, for growth and bone development and for reproduction. For vision the active vitamin appears to be retinal as the chromophore of both rods and cones is 11-cis-retinal which, in combination with the protein opsin, forms the photoreceptor rhodopsin. Retinoic acid is the active form associated with growth, differentiation, and transformation. Both all-trans and 9-cis retinoic acid act as a steroid hormone to affect cellular differentiation, especially for morphogenesis, reproduction and for immune responses. At... 

Mechanism of Action Modulates differentiation and proliferation of epithelial tissue, binds selectively to retinoic acid receptors. TherapeutkEffect Restores normal differentiation of the epidermis and promotes reduction of epidermal inflammation. Pharmacokinetics Minimal systemic absorption occurs through the skin. Binding to plasma proteins is greater than 99%. Metabolism is in the skin and liver. Elimination occurs through the fecal and renal pathways. Half-life 18 hr. 

Retinoid Hormones Retinoids are potent hormones that regulate the growth, survival, and differentiation of cells via nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, primarily in liver (see Fig. 10-21), and many tissues convert retinol to the hormone retinoic acid (RA). 

Vitamin A Retinol Retinal Retinoic acid p-Carotene Retinol Retinal Retinoic acid FAT-SOLUBLE Maintenance of reproduction Vision Promotion of growth Differentiation and maintenance of epithelial tissues Gene expression... 

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

Vitamin A and its analogues, in particular retinoic acid, are involved in the proliferation and differentiation of epithelial tissues and have continued to be used in the treatment of dermatological disorders such as acne, psoriasis and hyperkeratosis [133, 134]. Currently, much effort is being focused on... 

The value of cultured stem cells to toxicology is in their promise as a continuous source of cells that can be induced to express a chosen cell-type-specific mature phenotype. This achievement would address two current limitations in safety testing scarcity of metabolically competent human systems and use of experimental animals. Numerous culture additives and conditions have been identified that cause commitment and partial differentiation along specific lineages, such as retinoic-acid-induced neuronal commitment of mouse embryonic stem cells. However, definition of conditions that produce fully differentiated cells with cell-type-specific function quantitatively similar to that of intact tissue remains problematic and is a high-priority research area in toxicology. 

Retinoic acid is a metabolic product of vitamin A that supports the growth and differentiation of epithelial tissues. Retinoic acid is formed in the cytosol by the reversible oxidation of retinol to retinal, and the irreversible oxidation of retinal to retinoic acid. There is controversy as to whether retinal is oxidized by retinal dehydrogenase, which is linked to NAD+, or by retinal oxidase. 

Retinoic acid modulates gene expression and tissue differentiation, acting by way of nuclear receptors. Historically, there was confusion between the effects of deficiency of vitamins A and D by the 1950s, it was believed that the confusion had been resolved. Elucidation of the nuclear actions of the two vitamins has shown that, in many systems, the two act in concert, forming retinoid-vitamin D heterodimeric receptors hypervitaminosis A can antagonize the actions of vitamin D. 

Oxoretinol is synthesized from canthaxin (see Figure 2.2) and occurs in plasma. It binds to the retinoic acid nuclear receptor (but not the RXR) and is active in tissue differentiation. In the early embryo, the main biologically active retinoid is 4-oxoretinaldehyde, which both activates RARs and also acts as a precursor of oxo-retinoic acid and oxoretinol. 

Apart from the effects on vision, most of the effects of vitamin A deficiency (Section 2.4) involve derangements of cell proliferation and differentiation (squamous metaplasia and keratinization of epithelia), dedifferentiation, and loss of ciliated epithelia. Retinoic acid has both a general role in growth and a specific morphogenic role in development and tissue differentiation. These functions are the result of genomic actions, modulating gene expression by activation of nuclear receptors. Both deficiency and excess of retinoic acid cause severe developmental abnormalities. 

The structural design of retinoic acid receptors explains, at least in part, the pleiotropy of this class of receptors. It is a consequence of the combinatorial possibilities offered by heterodimerization. The many different functional units that can be formed by heterodimerization make it understandable why so many different gene response elements can be recognized. This, and a distinct spatiotemporal pattern of expression, both in the developing embryo and in differentiated tissues, suggests that each RAR and RXR isoform and each heterodimer formed may have a unique function. Pierre Chambon has directed attention to the large repertoire of combinatorial arrangements. These combina-... 

Retinol and retinoic acid are involved in growth and also in differentiation and maintenance of epithelial tissue. 

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