DIAZACHOLESTEROL-INDUCED ICHTHYOSIS IN THE HAIRLESS MOUSE .1. MORPHOLOGIC, HISTOCHEMICAL, AND LIPID BIOCHEMICAL-CHARACTERIZATION OF A NEW ANIMAL-MODEL

Abstract

Several drugs that interfere with sterol metabolism were associated with hyperkeratosis in man. 20,25-Diazacholesterol (30-60 mg/kg per day), administered to hairless mice that were otherwise given normal laboratory chow and water ad libitum, consistently produced ichthyosis after 6-9 wk, 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 3-10 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; 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 TLC and high pressure liquid chromatography. A syndrome of drug-induced ichthyosis in hairless mice that parallels the drug-induced syndrome in man is described. This syndrome is reversible and accompanied by distinctive abnormalities in cutaneous sterol metabolism. The diazacholesterol model may increase understanding of the pathogenesis of human keratinizing disorders and may provide a valuable analog for testing new forms of therapy, such as retinoids, for scaling dermatoses.