All trans-retinoic acid

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

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. 

CYP26 consists of three enzymes each representing a separate subfamily (Table 1) probably are all involved in retinoic acid hydroxylation. CYP26A1 is an all trans retinoic acid hydroxylase which degrades retinoic acid, an important signalling molecule for vertebrate development. It acts through retinoic acid receptors. The other CYP26 isozymes are also retinoic acid hydroxylases. 

Tretinoin, also referred to ATRA, which stands for all-trans-retinoic acid, is a retinoic acid that is not cytotoxic but promotes the maturation of early promyelocytic cells and is specific to the t(15 17) cytogenetic marker. The time to peak concentrations is 1 to 2 hours after an oral dose. The elimination half-life is 21 to 51 minutes.32 These maroon-and-gold capsules are dosed at 45 mg/m2 per day divided into two doses. The most significant side effect is the retinoic acid syndrome, which may occur anywhere from the first couple of days of therapy until the end of therapy and consists of symptoms of... 

FIGURE 20.2 The involvement of RARE on apo-lO -lycopenoic acid-transactivated RARp expression. Upper panel Diagram of the RARp reporter vector with wild type and mutated R AREs. Lower panel HeLa cells transfected with the RARp reporter vector and an internal control vector were treated with 5 pmol/I. of apo-lO -lycopenoic acid or 1 pmol/L of all-trans retinoic acid for 24h. Luciferase activities were measured by dual-luciferase reporter system. Values are means of SEM of three replicate assays., statistically significantly different, as compared with control in the same group, P < 0.05. (Adapted from Lian, F. et al., Carcinogenesis, 28, 1567, 2007. With permission.)... 

Liu, Y., Chang, R.L., Cui, X.X., Newmark, H.L. and Conney, A.H. 1997. Synergistic effects of curcumin on all-trans retinoic acid- and 1 alpha,25-dihydroxyvitamin D3-induced differentiation in human promyelocytic leukemia HL-60 cells. Oncol Res 9 19-29. 

The tritium-labelled 9-cri-retinoic acid [11,12-3H2], 96, the natural ligand for retinoid X receptor (RXR)83, has been produced84 by small-scale photoisomerization of all-trans-retinoic acid [11,12-3H2(N)], 97, followed by HPLC purification (equation 37). 

Granulocyte differentiation acute promyelocytic leukemia PBMCs (in vivo) Cultured bone marrow mononuclear cells (in vitro) All-trans retinoic acid (ATRA) Promoter analysis of ATRA response genes suggest molecular mechanism underlying ATRA-induced granulocytic differentiation [30]... 

Baltes S, Nau H, and Lampen A [2004] All-trans retinoic acid enhances differentiation and influences permeability of intestinal Caco-2 cells under serum-free conditions. Dev Growth Differentiation 46 503-514... 

M, Noelle RJ All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 2007 204 1765-1774. 

White JA, Guo YD, Baetz K, Beckett-Jones B, Bonasoro J, et al. 1996. Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase. J Biol Chem 271 29922-29927. 

White JA, Ramshaw H, Taimi M, Stangle W, Zhang A, et al. 2000. Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism. Proc Natl Acad Sci USA 97 6403-6408. 

H. Narahara, M. Tatsuta, H. lishi, M. Baba, N. Uedo, N. Sakai, H. Yano and S. Ishiguro, K-ras point mutation is associated with enhancement by deoxycholic acid of colon carcinogenesis induced by azoxymethane, but not with its attenuation by all-trans-retinoic acid, Int. J. Cancer, 2000, 88(2), 157. 

Lim S.-J. and Kim C.-K., Eormulation parameters determining the physicochemical characteristics of sohd hpid nanoparticles loaded with all-trans retinoic acid, Int. J. Pham., 243, 135, 2002. 

There are many retinol containing preparations to treat vitamin deficiency states. Retinoids are also used to treat dermatological diseases like acne, psoriasis, Darier s disease, and ichthyosis. Tretinoin, all-trans-retinoic acid, is a topical preparation while isotretinoin or 13-cis-retinoic acid, and etretinate are available for oral administration. 

Nau HJ (2001) Teratogenicity of isotretinoin revisited species variation and the role of all-trans-retinoic acid. J Am Acad Dermatol 45(5) S183-S187... 

Receptor for all-trans retinoic acid, RAR all-trans retinoic acid AGTTCA IR-0, DR-2,5 ER-8... 

Fig. 4.6. HRE structure of the RXR heterodimer. Shown is the consensus sequence of the HREs of the RXR heterodimers (see Fig. 4.7) and the different possible arrangements of the hexameric half-site sequences. The hexamers can be arranged palindromically as inverted repeats (a), as everted repeats (b), or as direct repeats (c). n indicates the number of base pairs that lie between the two hexamers. RXR receptor for 9-ds retinoic acid RAR receptor for all-trans retinoic acid T3R receptor for the T3 hormon PPAR peroxisome prohferator-activated receptor VDR receptor for vitamin D3.

The DNA binding element of the nuclear receptors for all-trans retinoic acid, for 9-cis retinoic acid, for the T3 hormone and for the vitamin D3 hormone usually exhibit a direct repeat of the recognition sequence, resulting in formation of heterodimers on the DNA (fig. 4.7b). One of the partners in the heterodimer is always the receptor for 9-cis retinoic acid, RXR, and which usually occupies the 5 side of the HRE. 

Ligands of the RXR-heterodimer group and the orphan receptors are chemically more diverse than the ligands of the steroid family. Representative hgands of this group are the retinoids all-trans retinoic acid, 9-cis retinoic acid, the T3 hormone and vitamin D3 (fig. 4.1). 

Initial studies on the receptors of all-trans retinoic acid, vitamin D3 and the T3-hor-mone assumed that these receptors boimd their HRE s in homodimeric form. It became clear with the discovery of the receptors for 9-cis retinoic acid that this simple... 

The receptors for all-trans retinoic acid, vitamin D3 and the Ts-hormone (as well as other receptors of this class, see table 4.1) usually perform their regulatory function as heterodimers. RXR plays a special role in the formation of heterodimers the receptor for 9-cis retinoic acid is usually one of the binding partners in the heterodimer. 

C8 Taxol, all-trans-retinoic acid Rifampin, barbiturates Trimethoprim... 

Acne and psoriasis Dermatologic problems such as acne and psoriasis are effectively treated with retinoic acid or its derivatives (see Figure 28.21). Mild cases of acne, Darier disease, and skri aging are treated with topical application of tretinoin (all trans retinoic acid), as well as benzoyl peroxide and antibiotics. [Note Tretinoin is too toxic for systemic administration and is confined to topical application.] In patients with severe recalcitrant cystic acre... 

Figure 2. General structure of retinoic acid (all trans-retinoic acid). Of the many derivatives tested (e.g., retinol, retinyl acetate), none has the "anti-tumor promoter efficacy, in vivo, as retinoic acid.

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

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