Retinoic acid receptors demonstration

ASBT has a complex regulatory system reflecting the importance of this transporter to bile-acid pool size and bile-acid synthesis rates. Hepatic nuclear factor la (HNF-la) is necessary for expression of ASBT as knockout mice showed no expression and had defective bile-acid transport.Conversely, FXR-null mice showed no difference in expression of ASBT, showing that FXR plays no part in regulation of ASBT. In man, HNF-la controls baseline promoter activity of the ASBT gene as the minimal construct with full promoter activity was found to have 3 HNF-la binding sites. These authors also showed that the promoter construct bound peroxisome proliferator activated receptor a (PPARa)/9 cis retinoic acid receptor heterodimer, demonstrating a link between bile-acid absorption and hepatic lipid metabolism mediated by PPARa. 

Adapalene, a third-generation retinoid, is a retinoid-mimetic com-ponnd (a naphthoic acid derivative), available as 0.1% gel, cream, alcoholic solntion, and pledgets. It has selective affinity for retinoic acid receptor (RAR) subtypes RAR- 8 and RAR-y fonnd in the epidermis," " " and has comedolytic, keratolytic, and anti-inflammatory activity. " " " Vehicle-controlled and comparative stndies have demonstrated the utility of adapalene in treatment of acne." " " Adapalene is indicated for mild to moderate acne vnlgaris. Adapalene 0.1% gel may be used as an alternative to tretinoin 0.025% gel to achieve better tolerability in some patients." " Adapalene coadministered with a topical or oral antibiotic represents arational therapy for moderate forms of acne."... 

Ethyl-2-(/J)-hydroxy-2-(T,2, 3. 4 -tetrahydro-T,T.4, 4 -tetramethyl-6 -naphthalenyl) acetate 53 (Figure 16.14) and the corresponding acid 54 were prepared as intermediates in the synthesis of the retinoic acid receptor gamma-specific agonist [86]. Enantioselective microbial reduction of ethyl 2-oxo-2-(T,2, 3. 4 -tetrahydro-T,T,4, 4 -tetramethyl-6-naphthalenyl) acetate 55 to alcohol 53 was carried out using Aureobasidiumpullulans SC 13849 at a 98% yield and with an EE of 96%. At the end of the reaction, hydroxyester 53 was adsorbed onto XAD-16 resin and, after filtration, recovered in 94% yield from the resin with acetonitrile extraction. The recovered (/ )-hydroxyester 53 was treated with Chirazyme L-2 or pig liver esterase to convert it to the corresponding (/ )-hydroxyacid 54 in quantitative yield. The enantioselective microbial reduction of ketoamide 55 to the corresponding (/ )-hydroxyamide 52 by A. pullulans SC 13849 has also been demonstrated [86]. 

Retinoids failed to activate NADPH oxidase in dibutyryl cAMP differentiated HL-60 cells (Seifert and SCHACHTELE 1988). In HL-60 cells retinoids have been found to potentiate formyl-methionyl-leucyl-phenylalanine-induced and phorbol myrist-ate acetate-induced 02 formation (Seifert and SchAchtele 1988). Using receptor specific retinoid analogues it was demonstrated that retinoid X receptor-retinoic acid receptor heterodimers mediate retinoid-induced differentiation of HL60 cells, while retinoid X receptor-retinoid X receptor homodimers mediate subsequent retinoid-mediated apoptosis (Nagy et al. 1995, Kizaki et al. 1996). 

The discovery of retinoic acid receptors in the late 1980 s was pivotal for our understanding of the mechanisms of retinoid action, because it was the first demonstration of the existence of a retinoid-responsive transcription factor. Both retinoic acid receptors (RARs) and retinoid X receptors (RXRs) have three different family members, a, P, and y, each encoded by different genes. KW-trans retinoic acid (/-RA) and its stereoisomer 9-cis retinoic acid (9c-RA), bind to RARs with similar high affinity [16]. The off-rates for t-RA binding to RAR-a, RAR-p, and RAR-y are similar [17]. However, for 9c-RA, the off-rates differ it is fastest with RAR-y and slowest with RAR p. Because of these differences, RARs tend to prefer t-RA when they are in the presence of mixtures of t-RA and 9c-RA. This is especially true for RAR-y, which demonstrates a strong preference for t-RA. t-RA does not bind to RXRs, only 9c-RA does [18, 19]. 

Impairment of the retinoid signal transduction pathways occurs as a result of prolonged UV exposure. Down regulation of nuclear receptors for Vitamin A occurs,269 resulting in a functional deficiency of Vitamin A. Application of Vitamin A derivatives would appear to be an obvious treatment modality. Topical application of Vitamin A does increase the HA in the epidermal layer, increasing the thickness of the HA meshwork after prolonged treatment.270 Vitamin A thus enhances repair, as can be demonstrated in photo-aged hairless mouse model.271 The decline in GAG, and in particular HA deposition that occurs with UVB irradiation, can be entirely prevented by retinoic acid treatment. 

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