All-frans-retinoic acid

Actinic keratoses were the first skin lesions to be treated topically with all-frans-retinoic acid. In various clinical trials, retinoids have been shown to be active in chemoprevention and treatment or prevention skin malignancies [2]. 

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.)... 

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. 

Acute promyelocytic leukemia Translocation PML/RARA PML/RARA All-frans retinoic acid, arsenic trioxide... 

Pierard-Franchimont, C., Goffin, V., and Pierard, G.E. Modulation of human stratum corneum properties by salicylic acid and all-frans-retinoic acid. Skin Pharmacol. Appl. Skin Physiol. 11 266-272 (1998). 

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. 

Takahashi K, Kukimoto I, Tokita K, Inageda K, Inoue S, Kontani K, Hoshino S, Nishina H, Kanaho Y, and Katada T (1995) Accumulation of cyclic ADP-ribose measured by a specific radioimmunoassay in differentiated human leukemic HL-60 cells with all-frans-retinoic acid. PEBS letters 371,204-8. 

All-frans-retinoic acid (Section 2.2.3.2) stimulates the synthesis of cADP-ribose in kidney cells in culture, apparently eis a result of the induction of CD38 (Beers et Eil., 1995 Takahashi et Eil., 1995) in ovariectomized rats, estradiol induces cytosolic ADP-ribosyl cycltise in the uterus, but not in estrogen unresponsive tissues (Chini et cd., 1997). If this induction of ADP-iibose cyclsise by esti ogens leads to significEuit depletion of nicotinamide nucleotides, it may provide an additional explcmation for the 2 1 excess of females to males in the incidence of peUsigra (Section 8.5). 

Beers KW, Chini EN, and Dousa TP (1995) All-frans-retinoic acid stimulates synthesis of... 

Chen H, Howald WN, and Juchau MR (2000) Biosynthesis of all-frans-retinoic acid from all-OB/ix-retinol catalysis of all-frans-retinol oxidation by human P-450 cytochromes. Drug Metabolism and Disposal 28,315-22. 

The hormonal forms of vitamin A are all-frans-retinoic acid and 9-cfs-retinoic acid. The hormonal form of vitamin D is 1,25-dihydroxyvitamin D3, and that of thyroid hormone is T3. These hormones act within the nucleus, where they bind to special proteins. These proteins are classed as transcription factors. Various transcription factors bind to the regulatory regions of all genes and influence the rate of transcription (Figure 9.60). Many genes are continuously transcribed, and here the term "basal level of transcription" is used to describe the rate of transcription. In cases where the gene is regulated, special transcription factors are used to enhance or inhibit the basal level of transcription. 

Cullimi, M. E., and Zile, M. H. (1985). Metabolism of all-frans-retinoic acid and aU-frans-retinyl acetate. /. Biol. Chem. 260,10590-10596. 

Koga H, Eujita I, and Miyazaki S (1997) Effects of all-frans-retinoic acid on superoxide generation in intact neutrophils and a cell-free system. British Journal of Haematology 97, 300-5. 

Tretinoin (All-frans-retinoic acid [ATRA], Vesenoid) APL... 

Schwartz, E.L. Hallam, S. Gallagher, R.E. Wiernik, P.H. Inhibition of all-frans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia. Biochem.PharmacoL, 1995, 50, 923-928... 

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.

Dermal drug administration is yet another pharmaceutical application of chitosan. Topical all-frans-retinoic acid (ATRA) is an effective treatment for serious malignant melanoma. However, this topical retinoid incites skin irritation in the wide majority of patients, rendering it an ineffective treat-ment. As evidenced by the research of Cattaneo and Demierre, chitosan gels avail themselves to sustained, topical release of ATRA. These studies showed that manipulation of the viscosity or chitosan concentration of the gel enabled control of percutaneous penetration of the drug in mouse skin samples. In addition, their clinical trials on healthy hiunan subjects indicated minimal erythema occurrence from application of 0.1% ATRA in 1% and 3% chitosan gel. 

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

Manolescu, D. C., Sima, A., and Bhat, P. V. 2010. All-frans retinoic acid lowers serum retinolbinding protein 4 concentrations and increases insulin sensitivity in diabetic mice. J Nutr 140 311-316. 

An ingenious binding assay for retinoic acid has been developed that depends on the high affinity of all-fran -retinoic acid-binding protein of rat testicular cytosol for its ligand (Shidoji and Hosoya, 1980). Prior treatment of the cytosol with Blue Sepharose reduced nonspecific binding. The detection limit was 3 ng retinoic acid. 

Use one culture as a positive control to check the response of the cells to retinoids For RA, a concentration of 5 x 10 Af all frans -retinoic acid (Sigma) should induce a response in the majority of cells. 

KL Salyers, ME Cullum, MH Zile. Glucuronidation of all-frans-retinoic acid in liposomal membranes. Biochim Biophys Acta 1152 328-334, 1993. 

Napoli JL, Pramanik BC, Williams JB, Dawson MI, Hobbs PD (1985) Quantification of retinoic acid by gas-liquid chromatography-mass spectrometry Total versus all-fran -retinoic acid in human plasma. J Lipid Res 26 387-392... 

Figure 1. Effects of an 8-day dietary repletion with all-fran -retinoic acid or retinol (ROH) on natural killer (NK) cell cytotoxicity in rats previously deficient in vitamin A (VA). Values are means SE of NK cell cytolytic activity (lytic units) per 10 NK cells (anti-NKR-Pl A" cells by flow cytometry). At the beginning of the repletion period, groups of five VA-deficient and five VA-sufficient rats were killed to confirm the low splenic NK cell activity of VA-deficient rats. Other VA-deficient animals were switched at this time to the RA-containing diet or to the retinol-sufficient diet. Eight days later, splenic NK cell cytotoxic activity and NK cell number were examined in four VA-deficient and five RA- and five ROH-repleted rats. Significantly different (P < 0.05) from VA-deficient rats. Significantly different (P < 0.05) from VA-deficient and VA-sufificient rats (Mann-Whitney U test). From reference [48] with permission.

---