Retinoids, mice treatment

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

Impairment of the retinoid signal transduction pathways occurs as a result of prolonged UV exposure. Down regulation of nuclear receptors for Vitamin A occurs,269 resulting in a functional deficiency of Vitamin A. Application of Vitamin A derivatives would appear to be an obvious treatment modality. Topical application of Vitamin A does increase the HA in the epidermal layer, increasing the thickness of the HA meshwork after prolonged treatment.270 Vitamin A thus enhances repair, as can be demonstrated in photo-aged hairless mouse model.271 The decline in GAG, and in particular HA deposition that occurs with UVB irradiation, can be entirely prevented by retinoic acid treatment. 

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. 

Several other experiments on cultured epidermal cells deserve mention. Newborn mouse epidermal cells cultured in semm-free defined medium respond to retinoid treatment in a dose-dependent manner, with an increase in both DNA and RNA synthesis (Spom et al., 1973). The response is extremely sensitive with an EDjq of 4 X 10 Af for all-rrmw-retinoic acid (Spom et al., 1976) and has been standardized in a sensitive assay for measurement of stmcture-function... 

Still other mechanisms of action might be considered. Rapaport etcd. (1982a,b) have shown that treatment of Swiss mouse 3T3 cells with retinoic acid significantly expands total cellular ATP pools in a dose-dependent manner, and that these changes alter functional compartmentalization of nuclear ATP pools (Schroder et al., 1983). It is proposed that these changes in nucleotide pools are directly responsible for the inhibition of DNA replication observed in these cells and that a similar mechanism might apply to other cells whose growth rate is modulated by retinoids (Schroder era/., 1983). 

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