Of retinoic acid

Tretinoin, the - -trans isomer of retinoic acid [302-79-4] was shown in the 1960s to be useful for the treatment of disorders associated with abnormal epithehal differentiation. 

Because of the presence of an extended polyene chain, the chemical and physical properties of the retinoids and carotenoids are dominated by this feature. Vitamin A and related substances are yellow compounds which are unstable in the presence of oxygen and light. This decay can be accelerated by heat and trace metals. Retinol is stable to base but is subject to acid-cataly2ed dehydration in the presence of dilute acids to yield anhydrovitamin A [1224-18-8] (16). Retro-vitamin A [16729-22-9] (17) is obtained by treatment of retinol in the presence of concentrated hydrobromic acid. In the case of retinoic acid and retinal, reisomerization is possible after conversion to appropriate derivatives such as the acid chloride or the hydroquinone adduct. Table 1 Hsts the physical properties of -carotene [7235-40-7] and vitamin A. 

Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10 940-954... 

Beside coactivators so-called corepressors exist that are bound to transcription factors such as nuclear receptors and inhibit the initiation of transcription. These factors include the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), which interact with nuclear receptors and serve as platforms for complexes containing histone deacetylases (HDACs). These enzymes cause the reversal of histone acetylation of histones leading to a tightening of chromatin and enhancing its inaccessibility for RNA polymerase containing complexes. 

Kang et al. [23] compared the clinical, histologic, and molecular responses of normal human skin to topical retinol with that of retinoic acid. Application of retinol and retinoic acid produced epidermal thickening. However, retinol produced less erythema compared with retinoic acid. The authors suggest that these data are compatible with the idea that retinol may he a pro-hormone of retinoic acid. 

Kang S, Duell EA, Fisher GJ, et al (1995) Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol 105 549-556... 

Carotenoid oxidation products are also supposed to have detrimental effects in vivo. As mentioned earlier, they are suspected to be involved in the adverse effects of high doses of 3-carotene supplementation in smokers and asbestos workers (CARET and ATBC studies) and in smoke-exposed ferrets. The mechanisms potentially involved have been investigated in vitro. P-Apo-8 -carotenal, an eccennic cleavage oxidation product of P-carotene, was shown to be a strong inducer of CYPlAl in rats, whereas P-carotene was not active. Cytochrome P450 (CYP 450) enzymes thus induced could enhance the activation of carcinogens and the destruction of retinoic acid. ... 

Base-induced elimination of sulphinate from homoallylic sulphones , from y-ketosulphones , and from 1,2-bissulphones has been used in synthetic sequences ranging from the preparation of retinoic acid and of its methyl ester , to a novel pentannulation sequence that leads to a range of cross-conjugated dienes , as exemplified by equation (69). The overall yield for the two steps was 63%. 

Napoli, J. L. and K. R. Race. 1988. Biogenesis of retinoic acid from beta-carotene. Differences between the metabolism of beta-carotene and retinal. J Biol Chem 263(33) 17372-17377. 

Prakash, P., C. Liu, K. Q. Hu et al. 2004. Beta-carotene and beta-apo-14 -carotenoic acid prevent the reduction of retinoic acid receptor beta in benzo[a]pyrene-treated normal human bronchial epithelial cells. J Nutr 134(3) 667-673. 

Gundersen T.E. and Blomhoff R., 1999. Online solid-phase extraction and isocratic separation of retinoic acid isomers in microbore column switching system. Meth Enzymol 299 430. 

Scheme 2.2-15. Synthesis of retinoic acid receptor agonists.

Hembree JR, Agarwal C, Beard RL, Chandraratna RA, and Eckert R [1996] Retinoid X receptor-specific retinoids inhibit the ability of retinoic acid receptor-specific retinoids to increase the level of insulin-like growth factor binding protein-3 in human ectocervical epithelial cells. Cancer Res 56 1794-1799... 

TGF-(3-treated T cells into pro-inflammatory Thl7 cells in favor of iT cells differentiation [67, 70]. The use of retinoic acid congeners as therapeutic agents in boosting oral tolerance is thus of intense current interest. 

Chen H, Fantel AG, Juchau MR. 2000. Catalysis of the 4-hydroxylation of retinoic acids by CYP3A7 in human fetal hepatic tissues. Drug Metab Dispos 28 1051-1057. 

Fujii H, Sato T, Kaneko S, Gotoh O, Fujii-Kuriyama Y, et al. 1997. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos. EMBO J 16 4163-4173. 

A. Goldbeter, D. Gonze, and O. Pourquie, Sharp developmental thresholds defined through bistability by antagonistic gradients of retinoic acid and FGF signaling. Submitted. 

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. 

Retinoic acid works through a family of retinoic acid receptors. Activated retinoic acid receptors act as transcription factors, just as activated steroid receptors do (chapter 20), and alter the transcription of genes affecting cell division and survival. This underlies both the teratogenic potential and the therapeutic utilities of these potent molecules. 

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 the absence of ligand, some nuclear hormone receptors associate with co-repressors, namely, SMRT (silencing mediator of retinoic acid and thyroid hormone receptors) and N-CoR (nuclear receptor co-repressor). Both, SMRT and N-CoR, recruit coregulatory protein SINS and histone deacetylases (HDACs) to form a large co-repressor complex that contains histone deacetylase activity, implicating histone deacetylation in transcriptional repression [52,53]. 

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