Androgen dependent skin disorders are important in clinical practice. Effective topical antiandrogens would lead to a breakthrough in their treatment. Although many attempts have been performed to develop such compounds, major successes have not been forthcoming. In the present study three existing antiandrogenic molecules have been compared with regard to their effect on androgen metabolism, receptor competition and on histological parameters in the hamster flank organ test. It appears that the effect on the hamster pigmented spot can be predicted on the basis of molecular mechanism. However, the effects on histological parameters are apparently dependent on additional factors such as metabolism of the active substance before reaching the sebaceous structure or limited penetration through the skin surface. The results indicate that in the development of new antiandrogens pre-screening can be performed with the aid of metabolic and receptor studies, while the histological parameters in the hamster flank organ test provide an animal model with a good predictive value.
Benzo(a)pyrene (BP)-metabolism in freshly isolated human hair follicles, cultured hair follicle keratinocytes and cells cultured from human bronchial epithelium was analysed by high performance liquid chromatography. All three types of tissues resulted in quantitatively comparable amounts of the most important organic solvent-soluble metabolites: 9,10-dihydrodiol-BP, 7,8-dihydrodiol-BP, quinones, and phenols. Besides these metabolites two early eluting compounds were detected: one possibly is BP-3-yl-hydrogen sulfate, the other probably consists of one or more tetrols. Water-soluble metabolites were quantitatively unimportant in both types of cultured cells and appeared to be primarily glucuronide and sulfate conjugates with the monohydroxides and the 7,8-dihydrodiol of BP. This metabolic pattern is compared to that of monocytes and lymphocytes which have been used frequently in population studies and with data from other types of human epithelial cells. It is concluded that human hair follicles and cultured keratinocytes from these organs are useful for detection of individual differences in carcinogen metabolism.
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