Retinoids, biological effects

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. ... 

The underlying mechanisms involved in the activities of carotenoid oxidation products are due either to a possible role as precursors of retinoids that would be the active species for positive effects or to their own specific activities. This latter case is illustrated by the activity of non-provitamin A carotenoid oxidation products such as those derived from lycopene. However, biological effects of carotenoid oxidation products other than retinoids are only hypothesized in vivo in humans, which hypothesis has been used as the basic principle to justify in vitro studies of these compounds. 

Retinoic Acid Receptor. Most of the biological effects of retinoids are mediated through the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Both all-/ran.s-retinoic acid and 9-d.v-rctinoic acid serve as agonists of RAR, while only 9-d.v-rctinoic acid functions as an agonist of RXR. The functional RAR exists as a heterodimer with RXR, while functional RXR exists as a homodimer. Methoprene is a juvenile hormone III analogue that mimics the activity of this insect hormone. 

The objectives of this chapter are to describe (l)retinoids that are currently in clinical use, including the adverse effects associated with the therapeutic use of these compounds (2) retinoid biosynthesis and metabolism (3) the basis of action of retinoids in molecular, cellular, and organismal contexts including vision and (4) new agents on the horizon of retinoid biology. 

Some isomers of trans-RA have been reported to exert very potent biological effects. Most noteworthy of these is 9-cis-RA (see Fig. 7,2), which was originally demonstrated to be a retinoid that activates both RARs and RXRs, whereas trans-RA activates only RAR family members (32-34). Levin and colleagues originally isolated [ H]9-cis-RA using RXRs to "trap it in cells fed [ Hl nzres-RA, implying... 

Retinoic acid and its natural and synthetic analogs (retinoids) exert a wide variety of biological effects by binding to or activating a specific receptor or sets of... 

The presence of a carboxyl terminal group is necessary for binding to CRABP and for retinoid activity [2]. However, comparison of other retinoid structural features shows a lack of correlation between retinoid potency and affinity for CRABP. Some potent retinoids do not bind to CRABP but do bind to nuclear retinoid receptors such as the RARs [146-149]. One such retinoid has been reported to be equally or more potent than RA but has lower affinity for RARs than RA [149]. It has been suggested that the reason for this apparent anomaly may be that the potency of RA is reduced because of its ability to bind to endogenous CRABP. It appears, therefore, that one of the functions of CRABP may be to regulate the amount of intracellular-active RA and thus control quantitatively the intensity of biological effects [149]. ... 

Retinoids are known for their importance in general growth, the growth and differentiation of epithelial tissues, visual function, and reproduction. The mechanism by which retinoids manifest all their biological effects is largely unknown. To facilitate additional basic research on the biochemistry and pharmacology of... 

As discussed in another chapter of this book, the specificity of various retinoids with respect to their biological effects and their use in different disease conditions can be demonstrated. 

If the biological effects of retinoids are mediated through their receptors, then alterations in the receptors are expected to be detrimental to the normal maintenance of structure and function of skin. In fact, in receptor gene knock-out mice and in mice in which dominant negative retinoid receptor transgenes are overexpressed, normal skin development and function are lost [24-27, 28]. Furthermore, when simultaneous null mutations of two RARs are introduced, the resultant phenotypic changes are similar to those observed in vitamin A-deficient animals [29]. 

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. 

Bexarotene (Targretin) belongs to a subclass of retinoids that selectively bind to and activates retinoid X receptors (RXRs), which have biological properties distinct from those of RARs. In vitro, bexarotene exerts antiproliferative effects on some tumor lines of hematopoietic and squamous cell origin. 

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