azacosterol and Ichthyosis

Topics: Animals; Azacosterol; Cholesterol; Etretinate; Female; Ichthyosis; Isotretinoin; Mice; Mice, Hairless; Skin; Tretinoin

Although the new synthetic retinoids are effective when administered systemically, they have not been shown to be effective as topical agents. We compared the topical activity of six synthetic retinoids (two arotinoids, etretinate, all-trans- and 13-cis-tetrazole-retinamide, isotretinoin, and tretinoin) on tail skin in the diazacholesterol-fed mouse model of ichthyosis. Responses were assessed clinically and by measurement of stratum corneum thickness. Although the arotinoids dramatically reduced scaling, they were toxic at concentrations above 0.1%, as was etretinate at 1.0% or greater. Lower concentrations were effective without producing local or systemic toxic reactions. Clinical responses were paralleled by equivalent decrements in stratum corneum thickness, which also permitted quantitative comparisons. The order of potency for the retinoids was as follows: arotinoids, etretinate, tetrazole-retinamides, tretinoin = isotretinoin, vehicle. These results demonstrate that (1) the synthetic retinoids hold promise as topical agents; (2) irritation is not an absolute requirement for topical retinoid activity; and (3) the diazacholesterol-fed mouse offers a new assay of topical retinoid potency in a well-defined animal model of ichthyosis.

Topics: Administration, Topical; Animals; Azacosterol; Cholesterol; Dose-Response Relationship, Drug; Etretinate; Ichthyosis; Male; Mice; Mice, Hairless; Retinoids; Structure-Activity Relationship; Tretinoin

Several drugs that interfere with sterol metabolism have been associated with hyperkeratosis in man. We found that 20,25-diazacholesterol (30 to 60 mg/kg/day), administered to hairless mice that were otherwise given normal laboratory chow and water ad libitum, consistently produced ichthyosis after 6 to 9 weeks, an effect that was reversible with removal of drug or with coadministration of a high cholesterol diet. Scaling was most pronounced over the tail, but some stratum corneum retention was noted over the entire skin surface. As measured in frozen sections, stratum corneum thickness was three to 10 times thicker in treated animals than in either controls or revertants. Oil red O-stained frozen sections and freeze fracture replicas revealed decreased stratum corneum membrane lipids in the diazacholesterol-treated animals, but this finding was not specific, since a similar deficit was found in control and revertant tail stratum corneum but not in the stratum corneum from other sites. Stratum corneum lipid extracts revealed reduced total free sterols, reduced cholesterol, accumulation of several normally absent sterol precursors, and increased glycosphingolipids on thin-layer chromatography and high pressure liquid chromatography. In summary, we describe a syndrome of drug-induced ichthyosis in hairless mice that parallels the drug-induced syndrome in man. This syndrome is reversible and accompanied by distinctive abnormalities in cutaneous sterol metabolism. The diazacholesterol model may further our understanding of the pathogenesis of human keratinizing disorders and may provide a valuable analogue for testing new forms of therapy, such as retinoids, for scaling dermatoses.

Topics: Animals; Azacosterol; Cholesterol; Disease Models, Animal; Freeze Fracturing; Glycosphingolipids; Ichthyosis; Lipids; Male; Mice; Mice, Hairless; Skin; Tail