Retinoic acid retinol conversion

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. 

Metabohc derivatives of the fat-soluble vitamin retinol, which was first described in 1913. These metabolites play a central role in the visual process where the primary photoevent is attended by conversion of ll-cA-retinal to all-rrans-retinal. The oxidized metabolite retinoic acid is an agonist in cell growth and proliferation. 

Retinol can be oxidized to retinal (6.2) and further to retinoic acid (6.3). Cis-trans isomerization can also occur, e.g. the conversion of all trans-retinal to 11-cis-retinal (6.4), which is important for vision. 

CRBP is thought to assure that retinol is metabolized by specific enzymes, while preventing metabolism by other enzymes. For example, by binding retinol, CRBP prevents excessive rates of conversion of retinol to retinoic acid (Napoli, 1996). 

Fig. 1. The structures of key retinoids and their precursors. Fish convert retinyl esters (e.g. retinyl palmitate (RP)) and carotenoids (e.g. /3-carotene) to retinol in the gut lumen prior to intestinal absorption. Retinyl esters (e.g. RP) stored in the liver are synthesized from retinol by lecithin retinol acyltransferase (LRAT) and acyl CoAiretinol acyltransferase (ARAT). The retinyl esters are mobilized through their conversion to retinol by retinyl ester hydrolase (REH), which is then transported in the circulation to various sites in the body. Retinol is further metabolized within specific tissues to retinal by alcohol dehydrogenases (ADH) or short-chain dehydrogenase/reductase. Retinal is converted to the two major biologically active forms of retinoic acid (RA) (all-trans and 9-cis RA). Retinaldehyde dehydrogenase 2 (Raldh2) synthesizes all-trans RA from all-trans precursors and 9-cis RA form 9-cis precursors.

The interaction between alcohol and vitamin A is complex. They have overlapping metabolic pathways a similar 2-step process is involved in the metabolism of both alcohol and vitamin A, with alcohol dehydrogenases and acetaldehyde dehydrogenases being implicated in the conversion of vitamin A to retinoic acid. Alcohol appears to act as a competitive inhibitor of vitamin A oxidation. In addition, chronic alcohol intake can induce cytochrome P450 isoenzymes that appear to increase the breakdown of vitamin A (retinol and retinoic acid) into more polar metabolites in the liver, which can cause hepatocyte death. So chronic alcohol consumption may enhance the intrinsic hepatotoxicity of high-dose vitamin A. Alcohol has also been shown to alter retinoid homoeostasis by increasing vitamin A mobilisation from the liver to extrahepatic tissues, which could result in depletion of hepatic stores of vitamin A. ... 

The most important natural retinoids are retinyl esters, retinol, and retinoic acid (RA). In the all-trans form, RA is the ligand for the nuclear RA receptors RAR- , RAR- ], and RAR- " in the 9-cis form, it is the ligand for the retinoid X receptors (RXRs), which form heterodimers with RARs to form the transcriptionally active complex that binds to RA response elements of target genes, as well as with the RARs see (2) for details and references). In the past, retinyl esters and retinol have been used for treating embryos (3,4) their effects on the developmental pattern probably depend on conversion to RA, although some other natural metabolites, such as 4-oxo-RA, may also be directly active (5). Most recent studies have used RA (mainly in the all-tra 5 form) for experimental purposes. 

Because of the inherent instability of labeled retinol, the usual practice is to store this compound as a more stable ester (e.g., retinyl acetate) or to keep it in the retinoic acid stage from which it can be prepared by reduction. From esters like the acetate, retinol can be obtained by hydrolysis with base or even by reduction with lithium aluminum hydride at low temperature. For this conversion, a trans-esterification in methanol is preferred, with catalysis by trace amounts of sodium methoxide followed by purification of the retinol by HPLC (Kaegi and Bupp, 1982). 

The metabolism of several other synthetic retinoids has been briefly examined but not analyzed to any great extent. Included are studies in rats of the hydrolysis of retinoic acid anhydride to retinoic acid (Premachandra and Cama, 1975), the conversion in hamsters of retinaldehyde acetylhydrazone (C8) and (V-acetyl-retinylamine (Bl) to retinol and retinyl esters (Roberts etal., 1978), the metabolism of 15-methyl retinone, 15-methylretinol, and 15,15-dimethylretinol (AlO) and the excretion of their metabolites in the bile and urine of rats (Tosukhowong and Olson, 1978), and the metabolism of 5,6-epoxy-5,6-dihydroretinol and retinaldehyde both in rats (Jungalwala and Cama, 1965 Lakshmanan et ai, 1965) and in cultured, spontaneously transformed mouse fibroblasts (Bhat et al., 1981). Because of the lack of extensive metabolic studies, these reactions are not discussed further here. 

The current leading hypothesis is that nuclear RAR and RXR play a direct role in this process. The retinoid receptors can be activated by physicochemical binding of free retinoic acid to RAR and RXR. Alternatively, covalent forms, such as retinoyl derivatives of RAR and RXR, might also exist. Interestingly, retinyl and retinoyl p-glucuronide stimulate the differentiations of HL-60 cells well without evident conversion to retinol and retinoic acid, respectively. Retinoic acid has also been implicated as a morphogen in embryonic development (18). The adverse effects of vitamin A deficiency on reproduction, growth, and the immune response, in all likelihood, are an expression of perturbations in the process of cellular differentiation. 

Lung Fibroblasts. The uptake kinetics of P-carotene into rat small intestinal cells (hBRIE 380) in culture and human lung fibroblasts and the conversion of p-carotene to retinol and retinoic acid were smdied by HPLC on a Beckman Ultrasphere ODS 5- xm (0.46 X 15 cm) column with a 12-min linear gradient of 100% methanol containing ammonium acetate (0.5%) to methanol/toluene (80 20) (213). 

Kurlandsky SB, Xiao JH, Duell EA, Voorhees JJ, Fisher GJ (1994) Biological activity of dW-trans retinol requires metabolic conversion to A -trans retinoic acid and is mediated through activation of nuclear retinoid receptors in human keratinocytes. J Biol Chem 269 32821-32827... 

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