18-Hydroxy-retinoic acid

OH-estradiol, 4-OH-estradiol, estrone, dihydrotestosterone, trans-retinoic acid, 4-hydroxy-retinoic acid, hyocholic acid, hyodeoxycholic, testosterone, LTB4... 

Hydroxy retinoic acid, hyocholic acid, hyodeoxycholic, testosterone, leukotriene B4,... 

CYP26 expression in normal human tracheobronchial epithelial cells was compared with that in human lung carcinoma cell lines (Kim et al. 2000). CYP26 mRNA could be induced by the retinoic acid receptor-selective retinoid 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid but not by the retinoid X receptor-selective retinoid SRI 1217 or the anti-activator-protein 1-selective retinoid SRI 1302. Retinoic acid receptor a-, P, and y-selective retinoids were able to induce CYP26 this induction was inhibited by the retinoic acid receptora-selective antagonist Ro41-5253. The induction of CYP26 correlated with increased biotransformation of retinoic acid into 18-hydroxy-, 4-OXO-, and 4-hydroxy-retinoic acid. 

H]Retinoic acid-treated human tracheobronchial epithelial cells contained several polar retinoic acid metabolites that coeluted with 4-oxo-, 4-hydroxy-, and 18-hydroxy-retinoic acid (Kim et al. 2000). 4-Hydroxy-retinoic acid could effectively induce MUC2 and MUC5AC mRNA expression in human tracheobronchial epithelial cells, indicating that it is an active retinoid able to induce mucous cell differentiation. 

Both al -trans- and IS-dy-retinoic-ll- H acid have been used to prepare the oxygenated metabolites. The acids were first esterified with diazomethane and then oxidized at C-4 with the aid of manganese dioxide to form the 4-oxo derivatives. Saponification with ethanolic potassium hydroxide then gave the 4-oxoretinoic acid (LXIV) (Fig. 17), which was reduced with sodium borohydride, yielding 4-hydroxy retinoic acid (LXV). 

Fig. 1.13 Negative mode single quadrupole MS spectra of sulfuric acid monoester of 3-hydroxy retinoic acid (A) electrospray, (B) atmospheric pressure chemical ionization.

Drug treatment of photoaged skin can be categorized as antioxidants, a-hydroxy acids and topical retinoids. Of these three approaches only topical retinoids, particularly retinaldehyde and alWrans-retinoic acid, have a well documented ability to restorethe repair... 

Sarcophytols A (46) and B (47) are simple cembranoids isolated from the Okinawan soft coral S. glaucum and have been reported to possess potent inhibitory activities against various classes of tumor promoters.70 71 Sarcophytol A (46) mediated dose-dependent diminution of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transformation of JB6 cells.72 When evaluated for potential to inhibit TPA-induced JB6 cell transformation, several of the sarcophine metabolites (48 to 58) mediated inhibitory responses greater than sarcophytol A (46) or sarcophine (45), most notably 7a-hydroxy-y8(19) deepoxysarcophine (50), which was comparable to 13-cz s-retinoic acid. These studies provide a basis for further development of novel furanocembranoids as anticancer agents. 

Figure 2.1. Major physiologically active retinoids. Relative molecular masses (Mr) retinol, 286.5 retinaldehyde, 284.4 retinoic acid, 300.4 13,14-dihydroxy-retinol, 318.5 4-oxoretinol, 301.5 retroretinol, 286.5 14-hydroxy-retroretinol, 302.5 anhydroretinol, 269.6 4-oxo-retinoic acid, 315.4 4-hydroxyretinoic acid, 316.4 dehydroretinol, 284.4 retinyl acetate, 328.5 and retinyl palmitate, 524.9. 

Future work includes defining endogenous plasma levels of 13-cis and all trans retinoic acid in an expanded population and determining whether normal plasma levels are affected by disease or nutritional state. Finally, the assay will be expanded to measure the major metabolites of retinoic acid (4-hydroxy, 4-oxo, glucuronide conjugates, etc.). 

Many retinaldehyde, retinol, and retinoic acid derivatives and analogues have been synthesized. The (3i )-3-hydroxy-derivatives (98), (99), and (100) were prepared from the optically active C15 Wittig salt (31).68 9-Bromoretinaldehyde (101 trans and 9-cis), 13-bromoretinaIdehyde (102 trans and ll-cis), phenyl-retinaldehyde (103 trans and 9-cis), and p-dimethylami nophenyl retinaldehyde (104 trans) have been prepared and used to make bacteriorhodopsin analogues.69 5,6-Dihydroretinaldehyde (105) and its desmethyl analogue (106) also formed... 

The conversion of frans-retinyl acetate into retinoic acid in hamster organ culture,262 and of cis- and trans-rzimoxc acid into the 5,6-epoxy- and 4-oxo-derivatives and their glucuronides has been demonstrated.263 264 Strains of Aspergillus niger metabolize ionones and related compounds to oxygenated derivatives, some of which may be useful intermediates for carotenoid synthesis. The asymmetric oxidation of p-ionone to (25, 6/ ,7/ )-2,7-epoxydihydro-a-ionone (218) has been demonstrated.265 (i )-4-Hydroxy-p-ionone (219 X = OH)... 

Frolik, C., A. Roberts, T. Tavela, P. Roller, D. Newton and M. Sporn. Isolation and identification of 4-hydroxy- and 4-oxoretinoic acid. In vitro metabolites of all-trans retinoic acid in hamster trachea and liver. Biochemistry 18 2092—2097, 1979. 

Arnhold, T., Tzimas, G., Wittfoht, W., Plonait, S. and Nau, H. (1996) Identification of 9-cis-retinoic acid, 9,13-di-cis-retinoic acid, and 14-hydroxy-4,14-retro-retinol in human plasma after liver consumption. Life Sciences, 59, PL169-177. 

Abbreviations HDCA hyodeoxycholic acid C20ap 3a-hydroxyetianic acid C20pp 3p-hydroxyetianic acid LA lithocholic acid atRA all tran retinoic acid atRAc all tran retinyl acetate 13-HODE 13-hydroxy-9,lloctadecadienoic acid 13-Oxo-ODE 13-oxo-9, 11-octadeca-dienoic acid nd not determined. 

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. 

Ethyl-2-(/J)-hydroxy-2-(T,2, 3. 4 -tetrahydro-T,T.4, 4 -tetramethyl-6 -naphthalenyl) acetate 53 (Figure 16.14) and the corresponding acid 54 were prepared as intermediates in the synthesis of the retinoic acid receptor gamma-specific agonist [86]. Enantioselective microbial reduction of ethyl 2-oxo-2-(T,2, 3. 4 -tetrahydro-T,T,4, 4 -tetramethyl-6-naphthalenyl) acetate 55 to alcohol 53 was carried out using Aureobasidiumpullulans SC 13849 at a 98% yield and with an EE of 96%. At the end of the reaction, hydroxyester 53 was adsorbed onto XAD-16 resin and, after filtration, recovered in 94% yield from the resin with acetonitrile extraction. The recovered (/ )-hydroxyester 53 was treated with Chirazyme L-2 or pig liver esterase to convert it to the corresponding (/ )-hydroxyacid 54 in quantitative yield. The enantioselective microbial reduction of ketoamide 55 to the corresponding (/ )-hydroxyamide 52 by A. pullulans SC 13849 has also been demonstrated [86]. 

Fig. 31.37 Substrates that form reactive glucuronides (1) ketoprofen (2) naproxen (3) clofibric acid (4) diclofenac (5) diflunisal (6) valproic acid (7) all-frans retinoic acid (8) bilirubin (9) A/-hydroxy-2-acetyTaminofluorene.

UGTIAI Bilirubin, estradiol (3-hydroxy), 2-hydroxyestrone, 2-hydroxyestradiol trans-retinoic acid, catechol estrogens (2- and 4-hydroxy)... 

Hydroxy estrone, 2-Hydroxy estradiol, 4-Hydroxy estradiol, estrone, dihydrotestosterone, tran -retinoic acid,... 

The first one that was recognized as being effective was retinoic acid. This was a prescription ointment drug until the over-the-counter product was approved in the mid-nineties, and proved efFective. Another is glycolic acid, which is available in makeup products or in more concentrated forms from physicians. There is also Kojic acid, alpha hydroxy acid, beta hydroxy acid, and the newest vitamin C products. Hydroquinone is another chemical that is used because it has a bleaching effect on the skin. 

The abbreviations used are HMG-CoA, 3-hydroxy-3-melhylglutaryl-CoA CAT, chloramphenicol acetyltransferase PPAR, peroxisome proliferator-activated receptor PPRE, peroxisome proliferator-responsive element NRRE, nuclear receptor responsive element RXR, retinoid X receptor hRXRa, human 9-cis-retinoic acid receptor a mPPARa, mouse peroxisome proliferator-activated receptor a COUP-TP, chicken ovalbumin upstream-promoter transcription factor, HNF-4, hepatocyte nuclear factor 4 EMSA, electrophoretic mobility shift analysis tk, thymidine kinase NEFA, nonesterified fatty acids... 

The most commonly used matrices for synthetic polymers are DHB (2,5-dihydroxybenzoic acid), HABA (2,(-4-hydroxyphenylazo)benzoic acid), lAA (3-j3-indoleacrylc acid), dithranol (1,8,9-trihydroxyanthracene), sinapinic acid (3,5-dimethoxy-4-hydroxy cinnamic acid), all trans-retinoic acid, and 5-chlorosalicylic acid. Exhaustive lists of useful matrices are available in the literature. ... 

Figure 2 Metabolic pathway of all-frans-retinoic acid (RA) to its hydroxy- and oxo-derivatives by cytochrome P450 (CYPs).

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