Retinoid receptors receptor subtypes

Jones, B., C. Ohno, G. Allenby, M. Boffa, A. Levin, J. Grippo and M. Petkovich. New retinoid X receptor subtypes in zebrafish (Danio rerio) differentially modulate transcription and do not bind 9-cis retinoic acid. Mol. Cell. Biol. 15 5226-5234, 1995. 

Bexarotene is a retinoid that binds and activates retinoid X receptor subtypes (RXRot, RXRp, RXRy). Once activated, these receptors function as transaiption factors that regulate the expression of genes that control cellular differentiation and proliferation, inhibit the growth in vitro of some tumor cell lines of hanatopoietic and squamous cell origin, and induce tumor regression in vivo in some animal models. Bexarotene is indicated in refractory cutaneous T-ceU lymphoma. 

Treatment of animals with large doses of retinol stimulated Kupffer cell functions including phagocytic activity and release of tumour necrosis factor and superoxide anion (Oj ) (Mobley et al. 1991). Ohata et al. (2000) reported mRNA by rat Kupffer cells of retinoic acid receptor and retinoid X receptor subtypes and their binding activities to the retinoic acid responsive element or retinoid X responsive element. 

Future generations of such receptor subtype-selective retinoids or also retinobenzoic acids [3] may provide clinicians with more specific and less toxic diugs for dermatologic therapy. 

Retinoids (i.e., tretinoin and tazarotene) mediate cellular responses primarily through activation of nuclear retinoid receptors [rr]. There are two types of nuclear retinoic acid receptors the retinoic acid receptors (RARs) and the retinoid X receptors. Each type of receptor contains three receptor subtypes alpha, beta, and gamma [rr, 11]. Among the commonly prescribed retinoids, tretinoin activates the RARs alpha, beta, and gamma directly, and the retinoid X receptors indirectly (through conversion of tretinoin to 9-cis-retinoic acid) [rr, 13]. Conversely,... 

Studies with knockout mutant mice lacking one or another of the retinoid receptors suggest that there is some degree of redundancy or overlap between the receptor subtypes, and that RARy is especiallyimportant in the teratogenic actions of retinoids (Section 2.5.1.1 Mark et al., 1999 Maden, 2000) ... 

The multipUcity of possible combinations of homodimers and heterodimers of RAR and RXR subtypes, and the various possible RXR heterodimers with other receptors, permits a wide variety of active retinoid receptor complexes that bind to different response elements on DNA. Unlike most hormone response elements on DNA, which are palindromic and bind a symmetrical receptor homodimer, the most common type of retinoid response element is a direct repeat purine-G-(G or T)-T-C-A-(Xn)-purine-G-(G or T)-T-C-A, in which the spacer (Xn) is commonly 5 base pairs, but may be 1 or 2. There are also more complex retinoid response elements, including palindromic and inverted palindromic repeats, as well as hexameric motifs with variable spacing. This means that a wide variety of different genes may be regulated differendy in response to retinoids. 

The doses of retinol that are protective in animals are in the toxic range (Section 2.5.1) and are unlikely to be useful in cancer therapy or prevention. A number of synthetic retinoids have been developed, in a search for compounds that show anticancer activity, but are metabolized, stored, and transported differently, or bind to different subtypes of retinoid receptor and are less toxic. RXR-selective ligands are less toxic and more active in animal cancer models than RAR ligands (Lippman and Lotan, 2000). Fenretinamide, and possibly other retinoids that have antitumor activity, exerts at least part of its action by induction of apoptosis by a receptor-independent mechanism (Wu et al., 2001). 

The present and future efforts of medicinal chemists in the development of novel retinoid compounds are discussed in this section. This body of work should ultimately lead to receptor and receptor subtype-selective agonists and antagonists and novel compounds that block proliferative signaling processes. 

As discussed in a previous section, the systemic and topical toxicity, as well as the teratogenicity of retinoids, limits the clinical usefulness of these compounds. The general opinion of both basic scientists and clinicians is that these toxicities may be mitigated by the development of receptor subtype-selective retinoids. Although this may ultimately be proven to be true, there is currently little factual basis for this opinion, at least with respect to the RAR subtypes, because it has been quite difficult to separate clinical efficacy from toxicity. Nonetheless, this remains a noble goal in the continued development of receptor sub-type-selective retinoids. 

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."... 

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