Retinoic acid oxidation

Brady Clark K, Howard JA, Oyler A. Retinoic acid oxidation at high oxygen pressure evidence for spin-forbidden direct addition of triplet molecular oxygen. J Am Chem Soc 1997 119 9560-9561. 

Figure 6.6 indicates the various reactions typical of vitamin Av Retinoic acid, oxidized trans-retinal, is apparently involved in epithelial cell physiology. Retinol phosphate, trans-retinol esterified with a phosphate residue, associates with various membrane structures through its hydrophobic isoprenoid residue, leaving its hydrophilic phosphate group in contact with the aqueous environment. It serves as an anchor for growing oligosaccharide chains in the same manner as dolichol phosphate does (see Chapter 18). 

However, the relevance of these transformations to retinoic acid homeostasis in target tissues is not clear. White et probed a panel of mRNAs from mammalian cell lines with a cDNA from a zebrafish P450 shown to be involved in retinoic acid-inducible retinoic acid oxidation and characterized P450 26A1 (ref [1391]). The heterologously expressed enzyme converted all-traws-retinoic acid to the 4-hydroxy-, and 4-oxo-, and 18-hydroxy products. The turnover numbers are unknown because the amount of P450 was not quantified, but the enzyme is clearly able to catalyze the oxidation of sub-p,M additions of all-fraris-retinoic acid. Apparently other retinoic acid isomers are not substrates. 

Although all-tran5-retinoic add can be oxidized by P450 3A subfamily enzymes and P450 2C8, P450 26A1 is the piedominant enzyme involved in retinoic acid oxidation [2508],... 

Ross, A. C. 2003. Retinoid Production and Catabolism Role of Diet in Regulating Retinol Esterification and Retinoic Acid Oxidation. J Nutr 133, no 1 291s-96s. 

Ross AC (2003) Retinoid production and catabolism Role of diet in regulating retinol esterification and retinoic acid oxidation. Journal of Nutrition 133(suppl) 291S-296S. 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

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. ... 

Carotenoid oxidation products are also supposed to have detrimental effects in vivo. As mentioned earlier, they are suspected to be involved in the adverse effects of high doses of 3-carotene supplementation in smokers and asbestos workers (CARET and ATBC studies) and in smoke-exposed ferrets. The mechanisms potentially involved have been investigated in vitro. P-Apo-8 -carotenal, an eccennic cleavage oxidation product of P-carotene, was shown to be a strong inducer of CYPlAl in rats, whereas P-carotene was not active. Cytochrome P450 (CYP 450) enzymes thus induced could enhance the activation of carcinogens and the destruction of retinoic acid. ... 

Panzella, L, Manini, P, Napolitano, A, and d Ischia, M, 2004. Free radical oxidation of (E)-retinoic acid by the Fenton reagent Competing epoxidation and oxidative breakdown pathways and novel products of 5,6-epoxyretinoic acid transformation. ChemRes Toxicol 17, 1716-1724. 

FIGURE 20.1 Schematic illustration of lycopene metabolic pathway by CM02. (a) 5-cis Lycopene and 13-cis lycopene are preferentially cleaved by CM02 at 9, 10 -double bond. The cleavage product, apo-lO -lycopenal, can be further oxidized to apo-lO -lycopenol or reduced to apo-lO -lycopenoic acid, depending on the presence of NAD+ or NADH. (b) Chemical structures of apo-lO -lycopenoic acid, acyclo-retinoic acid, and all-frans retinoic acid. (Adapted from Hu, K.Q. et al., J. Biol. Chem., 281, 19327, 2006. With permission.)... 

Wang, X. D., R. M. Russell, C. Liu et al. 1996. Beta-oxidation in rabbit liver in vitro and in the perfused ferret liver contributes to retinoic acid biosynthesis from beta-apocarotenoic acids. J Biol Chem 271 (43) 26490-26498. 

There are several alternative pathways associated with the balance between proliferation and apoptosis that are affected by lycopene treatment, especially the insulin-like growth factor (IGF) signaling pathway. Another is the possibility that lycopene or one of its breakdown products has retinoid activity. Kotake-Nara et al. compared acyclo-retinoic acid, an in vitro oxidation product of lycopene, to four actively researched anticarcinogenic retinoids. Acycloretinoic acid was found to more actively reduce PC-3 and DU-145 cell viabilities (but not LNCaP) through apoptosis in a medium already containing small amounts of natural retinoids. But study concentrations were 20 pM, far above physiologically relevant lycopene concentrations, let alone the smaller concentration of one of its breakdown products. Acycloretinoic acid had a very low affinity for the retinoid X receptors (RXR) and retinoic acid receptors (RAR) receptors (Kotake-Nara et al. 2002). 

Retinoic acid Retinol (vitamin A) oxidation Zn finger ( ) ... 

This reaction was also used in a synthesis of 13-cis-retinoic acid.2 Thus reduction of 3 under the same conditions gives the triethylsilyl ether (4) of 13-cis-retinol, with retention of the geometry of the terminal double bond. This product can be converted to 13-cis-retinoic acid by deprotection and oxidation (60% yield). 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

Here we have another simple chemical transformation, the oxidation of the aldehyde group in retinal to the carboxyl group of retinoic acid. Although the chemical change is simple, the physiology is profoundly different. Retinoic acid has nothing to do with vision but a lot to do with development and differentiation. Here we have yet another example of the sensitive interdependence of chemical structure and biological function. 

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. 

Retinyl esters and the P-carotene are incorporated into chylomicrons and taken up mainly by hepatocytes. In the liver retinol may be stored in stellate cells as retinyl esters, oxidized to retinoic acid or liberated into cells bound to retinol-binding proteins (RBP). All E retinoic acid and its 9Z isomer have an affinity for nuclear receptors. They activate the transcription and bind as dimers to specific nucleotide sequences, present in promoters of target genes. 

These authors also described a three-step synthesis of 13Z-retinoic acid [56], The obtained hydroxydihydropyrane (66%) was oxidized either by Jones s reagent (CrC>3, water, H2SO4, 90%) or Corey s reagent (pyridinium chlorochromate (PCC), 65%). Finally, the dihydropyranone was transformed into retinoic acid (as a mixture of 9E, 13Z, and 9Z,13Z), by /BuOK, according to a known procedure [57], Fig. (26). 

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. 

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