Retinoic acid biologic activity

The existence of biologically active metabolites of retinoic acid has been reported. Krishnamurthy et al. (1963) detected a fat-soluble metabolite of retinoic acid, which displayed biological activity in a rat curative assay, in the liver of chicks administered a 10-mg oral dose of the parent retinoid. Similarly, Wolf et al. (1963) reported that an intestinal metabolite, isolated from retinoid-deficient rats injected with labeled retinoic acid, was active in restoring to normal levels the mucopolysaccharide biosynthesis in retinoid-deficient rat intestinal cell-free particle suspensions. The same laboratory also described a decarboxy-lated metabolite of both retinol and retinoic acid that was isolated from the intestine of retinoid-deficient rats administered retinol or retinoic acid. This compound, which appeared to have both carboxyl and hydroxyl functional groups, was biologically active in a growth assay (Yagishita et al., 1964). In... 

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 physiological hormone for the RARs is all-frans-retinoic acid RA 221 and that for the RXRs is its geometric isomer, 9-czs-retinoic acid (9-czs-RA 222) [320]. However, these polyolefinic hormones are of only limited use in elucidating the precise biological roles of each receptor family. Synthetic ligands that specifically activate only the RXR or RAR hormonal pathway and which cannot be converted into forms that activate the other pathway would be of much greater use in this regard. 

The leveisal of the oxidative pathway of vitamin A (retinol —r retinal —>-retinoic add) does not occur in the body, When retinoic acid is feci to animals, even in relatively large doses, there is no storage and, in fact, die molecule is rapidly metabolized and cannot be found several hours after administration. The metabolic products have not been fully identified. Several fractions from liver or intestine, isolated after administering retinoic add marked with carbon-14, have been shown to have biological activity. 

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. 

McCormick, A.M., Napoli, J.L., Schnoes, H.K., DeLuca, H.F. 1978. Isolation and identification of 5,6-epoxyretinoic acid a biologically active metabolite of retinoic acid. Biochemistry 17, 4085 1090. 

Roalsvig, X, Honeyman, J.A., Tortola-Ni, D.R., Reczek, P. R., Mansuri, M.M., Starrett, J.E., Jr. Retinoic acid receptor beta,gamma-selective ligands synthesis and biological activity of 6-substituted 2-naphthoic add retinoids. J. Med. Chem. 

Oxoretinol is synthesized from canthaxin (see Figure 2.2) and occurs in plasma. It binds to the retinoic acid nuclear receptor (but not the RXR) and is active in tissue differentiation. In the early embryo, the main biologically active retinoid is 4-oxoretinaldehyde, which both activates RARs and also acts as a precursor of oxo-retinoic acid and oxoretinol. 

Miller DA and DeLucaHF (1986) Biosynthesis ofretinoyl-beta-glucuronide, a biologically active metabolite of all-frans-retinoic acid. Archives of Biochemistry and Biophysics 244, 179-86. 

Johnson AT, Wang L, Standeven AM et al (1999) Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorg Med Chem 7 1321-1338... 

A-2 Vitamin A consists of three biologically active molecules, retinol, retinal (retinaldehyde) and retinoic acid. Each of these compounds are derived from a group of molecules know as carotenoids also referred to as the provitamin A. Beta-carotene, which consists of two molecules of retinal linked at their aldehyde ends. 

After administration of a -trans-, 3-cis- or 9-cw-retinoic acid, the respective retinoyl glu-curonides (RAG) have been identified as the major metabolite in most mammal models including the human system. Like R A, RAG is biologically active in promoting the growth of vitamin A-deficient rats [187] and in the induction of differentiation of, e. g., HL-60 cells [188], but unlike RA, RAG is less cytotoxic and teratogenic. Like RA, RAG is also effective in the topical treatment of human acne [189], but unlike RA, it does not produce any side effects associated with RA therapy [189]. 

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