Retinoic acid functions

Unusual features of vitamin A as observed by some investigators include (1) decreases serum cholesterol in large-quantity administration (chicks) (2) dietary protein required to mobilize liver reserves of vitamin A (3) decreased quantities in tumors (4) coenzynre Q10 accumulates in A-deficient rat liver (5) Ubichromenol-50 accumulation in A-deficient rat liver (6) retinoic acid functions as vitamin A except for visual and reproductive functions (7) anti-infection properties and anti-allergic properties (8) decreases basal metabolism (9) detoxification of poisons in the liver aided by vitamin A and (10) vitamin A is involved in triose —> glucose conversions. 

Vitamin A is a fat soluble vitamin derived from carotene. The alcohol form of vitamin A, retinol, is the storage form in the body. The aldehyde form, retinal, has a role in vision. The acid form, retinoic acid, functions in embryonic development. Vitamin A acts to some extent in the body as an antioxidant, protecting against oxidative damage. 

Within cells, vitamin A (retinol, retinal, retinoic acid) functions mainly in vision, cellular differentiation, and embryogenesis. The adverse effects of vitamin A deficiency on complex physiological processes such as reproduction and the immvme response result primarily from defective cellular differentiation. 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

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 (retinol) and retinoic acid are carotenoid oxidation compounds that are very important for human health. The main functions of retinoids relate to vision and cellular differentiation. With the exception of retinoids, it was only about 10 years ago that other carotenoid oxidation products were first thought to possibly exert biological effects in humans and were implicated in the prevention - or promotion of degenerative diseases. A review on this subject was recently published. ... 

In another recent example, Hashimoto reported photoaffinity experiments on retinoic acid receptors (RAR). Retinoic acid plays a critical role in cell proliferation and differentiation. RARs belong to the superfamily of nuclear/ thyroid hormone receptors. They consist of six transmembrane domains (A-F) which is a general feature of these receptors. The A/B domains have an autonomous transactivation function while the C-domain contains the Zn-finger, which binds to DNA. The large E-domain participates in ligand binding, dimerization, and ligand dependent transactivation. Finally, D- and F-domains help the orientation and stabilization of the E-domain. 

Histochemical studies of bone marrow samples show that peroxidase-containing granules are detectable in promyelocytes. The human promyelo-cytic leukaemia cell line HL-60 grows easily in culture, and the cells resemble promyelocytes both structurally and functionally. Furthermore, they can be induced to differentiate in vitro upon addition of various agents, such as retinoic acid and phorbol esters, and these differentiated cells resemble more mature forms of neutrophils. HL-60 cells possess almost the same amount of myeloperoxidase (4.4 fig per 106 cells) as mature neutrophils, and the enzyme purified from these cells has the same subunit structure. The cells thus actively synthesise the enzyme only until they are induced to differentiate. This cell line has been extensively used to study the molecular events controlling the expression of enzymes such as myeloperoxidase, and also to investigate the molecular controls that lead to a cessation of their expression. 

Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-P and retinoic acid-dependent mechanism. J Exp Med 2007 204 1757-1764. 

Here we have another simple chemical transformation, the oxidation of the aldehyde group in retinal to the carboxyl group of retinoic acid. Although the chemical change is simple, the physiology is profoundly different. Retinoic acid has nothing to do with vision but a lot to do with development and differentiation. Here we have yet another example of the sensitive interdependence of chemical structure and biological function. 

Isoprenoids that have hormonal and signaling functions form an important group. These include steroid hormones (1 = 6) and retinoate (the anion of retinoic acid 1 = 3) in vertebrates, and juvenile hormone (1 =3) in arthropods. Some plant hormones also belong to the isoprenoids—e.g., the cytokinins, absci-sic acid, and brassinosteroids. 

In addition to the receptors mentioned in A, the family of steroid receptors also includes the product of the oncogene erb-A (see p. 398), the receptor for the environmental toxin dioxin, and other proteins for which a distinct hormone ligand has not been identified (known as orphan receptors ). Several steroid receptors—e. g., the retinoic acid receptor-form functional heterodimers with orphan receptors. 

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