Retinoic acid formation

Mertz JR, Shang E, Pianedosi R, Wei S, Wolgemuth DJ, Blaner WS (1997) Identification and characterization of a stereospecific human enzyme that catalyzes 9-cw-retinol oxidation a possible role in 9-cw-retinoic acid formation. 7 Bio/ Chem 212 11 744-11 749... 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ (1993) Restoration of collagen formation in photodamaged human skin by tretinoin (retinoic acid) N Engl J Med 329 ... 

Goralczyk, R., Wertz, K., Lenz, B. et al. 2005. Beta-carotene interaction with NNK in the AJ-mouse model Effects on cell proliferation, tumor formation and retinoic acid responsive genes. Biochim Biophys Acta 1740 179-188. 

However, here, too much of a good thing is not so hot. If retinoic acid is administered systemically during embryo formation (in experimental animals to be sure), severe malformations result in the offspring. Thus, retinoic acid is a teratogen. 

Vitamin A is essential for growth and development of cells and tissues. In its active form, retinoic acid (RA), it controls the regular differentiation as a ligand for retinoic acid receptors (RAR, RXR) and is involved in the integration (gap junction formation) of cell formations (Biesalski, 1996 Biesalski et al, 1999). Vitamin A plays a substantial role, especially in the respiratory epithelium and the lung. During moderate vitamin A deficiency, the incidence for diseases of the respiratory tract is considerably increased and repeated respiratory infections can be influenced therapeutically by a moderate vitamin A supplementation (Biesalski et ah, 2001 Greenberg et ah, 1997 John et ah, 1997). 

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. 

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. 

Retinoic acid is insoluble in water but soluble in many organic solvents. It is susceptible to oxidation and ester formation, particularly when exposed to light. Topically applied retinoic acid remains chiefly in the epidermis, with less than 10% absorption into the circulation. The small quantities of retinoic acid absorbed following topical application are metabolized by the liver and excreted in bile and urine. 

Fig. 12 Substances used for complex formation and nanoparticles, (retinoic acid) All-trans retinoic acid, (PLA) poly(-L-arginine), (PLH) poly(-L-histidine), (PLL) poly(-L-ly-sine). As dispersing agent a tri-block copolymer was used. It consisted of ethylene oxide and propylene oxide (Poloxamer 188). Reprinted with permission from [142]. Copyright 2000 American Chemical Society...

In conclusion, it was found that complexes of poly(ethylene oxide)-h-poly(L-lysine) with retinoic acid with short poly(L-lysine) segments of 18 and 30 monomers form core shell micelles. The cores of the micelles contain a lamellar smectic A-like structure, formed by a poly(L-lysine) retinoate complex, which is surrounded by a corona of poly(ethylene oxide). Although the poly(L-lysine) chains are relatively short, they adopt an a-helical conformation to a pH as low as 9. This effective stabilization of the a-helix structure seems to be due to the formation of a protective surrounding coat of retinoate and a shell of poly(ethylene oxide). 

The immobilization of retinoic acid by branched PEI with different molecular weights (6 102 to 2xl06 g/mol) is described in the following section. The main interest is on the formation of mesomorphous structures, the release of retinoic acid from its complexes and the formation of nanoparticles. 

Some teratoma cell lines isolated by method 1, e.g. the F9 cell line, have almost lost their capacity to differentiate. However, Strickland and Mahdavi (1978) have shown that differentation may be induced with retinoic acid at 10 9M. Again endoderm formation is detected by formation of plasminogen activator, a- foetoprotein, or by use of immunological markers (Adamson and Grover, 1983). 

It was found that formation of the 6-cyclodextrin inclusion complex improved the compound solubility from less than 0.5 mg/mL to 160 mg/mL, eliminating the formulation problems associated with solubility concerns [65]. Although retinoic acid does exhibit intrinsic CD when dissolved in dimethyl sulfoxide, the CD spectrum is drastically upon formation of the cyclodextrin inclusion complex (see Figure 10). That CD can be measured in the absorption bands located at 350 and 400 nm can be taken as evidence that it is the conjugated sidechain of the retinoic acid solute which becomes included in the cavity of the cyclodextrin host system. 

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