Retinoid

Vitamin A constitutes the most significant sector of the commercial retinoid market and is used primarily in the feed area. In the pharmaceutical area, there are several important therapeutic dermatologic agents which stmcturaHy resemble vitamin A and they are depicted in Figure 2 (see Pharmaceuticals). The carotenoids as provitamin A compounds also represent an important commercial class of compounds with P-carotene [7235-40-7] (10) occupying the central role (Fig. 3) (9). 

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. 

More specific methods involve chromatographic separation of the retinoids and carotenoids followed by an appropriate detection method. This subject has been reviewed (57). Typically, hplc techniques are used and are coupled with detection by uv. For the retinoids, fluorescent detection is possible and picogram quantities of retinol in plasma have been measured (58—62). These techniques are particularly powerful for the separation of isomers. Owing to the thermal lability of these compounds, gc methods have also been used but to a lesser extent. Recently, the utiUty of cool-on-column injection methods for these materials has been demonstrated (63). 

Owing to the light and air sensitivity of the carotenoids and retinoids, sample handling is a critical issue. It is recommended to conduct extraction of these materials with peroxide-free solvents, to store biological samples at —70° C under argon and in the dark, to perform the analysis under yellow light, and to use reference compounds of high purity (57). 

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). 

A. P. De Leenheer, W. F. Lambert, and H. J. NeHs, eds.. Retinoids and Carotenoids iu Modem Chromatographic Ana/ysis of the Vitamins, Marcel Dekker, New York, 1992. 

M. A. Livrea and G. VidaU, eds.. Retinoids From Basic Science to C/inica/App/ications, Birkhauser Vedag, Germany, 1994. 

The retinoid isotretinoin (68) has been found to reduce the incidence of secondary malignancies in patients treated for head and neck cancer. In addition, the use of trans-m m.oic acid in patients having M3 leukemia has been reported to induce complete, although temporary, remissions (32). 

The retinoid X receptor forms heterodimers that recognize tandem repeats with variable spacings... 

Benzimidazole and benzodiazepines derivatives as retinoid antagonists 96YZ928. 

The retinoids share with certain steroid hormones the dis-I inetion of belonging to the few classes of substances capable 111 powerful positive influence on cell growth and differentia-... 

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

Figure 5.2 Schematic representation of the final column-switching system (a) foi ward-flush position (b) back-flush position (further details are given in the text). Reprinted from Journal of Chromatography, A 828, A. K. Sakhi et al. Quantitative determination of endogenous retinoids in mouse embiyos by high-performance liquid cliromatography with on-line solid-phase exti action, column switcliing and electi ochemical detection , pp. 451 -460, copyright 1998, with permission from Elsevier Science.

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

The antagonist-induced conformation of nuclear hormone receptors attracts co-repressors like Nco/SMRT (nuclear hormone receptor co-repressor/silencing mediator of retinoid and thyroid receptors) which further recruit other nuclear proteins with histone deacetylase activity. Their action leads to chromatin condensation, thus preventing the general transcription apparatus from binding to promoter regions. 

CYP1B1 (chromosome 5) has been linked to primary congenital glaucoma. CYP1B1 is not regularly expressed in liver but is often found in various kinds of tumours. It metabolizes retinoids and many aromatic amines and PAHs to potentially carcinogenic products. 

Cell Cycle Control Diabetes Mellitus Retinoids... 

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