Sebocytes are the key regulators of androgen homeostasis in human skin

The mRNA expression patterns of the androgen receptor and the androgen meta bolizing enzymes 3 beta -hydroxysteroid dehydrogenase/Delta (5-4)-siomerase , 17 beta -hydroxysteroid dehydrogenase, 5 alpha -reductase, and 3 alpha -h ydroxysteroid dehydrogenase were investigated in three different cell popul ations originating from human skin, SZ95 sebocytes, HaCaT keratinocytes, an d MeWo melanoma cells, by means of reverse transcription polymerase chain r eaction. Restriction analysis of cDNA fragments was performed to identify i sozymes of 3 beta -hydroxysteroid dehydrogenase/Delta (5-4)-isomerase and 3 alpha -hydroxysteroid dehydrogenase. In addition, H-3-dihydroepiandrostero ne and H-3-testosterone were used as substrates to determine the metabolic activity of these enzymes in SZ95 sebocytes, primary sebocyte cultures, and HaCaT keratinocytes, Furthermore, the effects of the selective 5 alpha -re ductase type 1 and 2 inhibitors, 4,7 beta -dimethyl-4-aza-5 alpha -cholesta n-3-one and dihydrofinasteride, respectively, and of the 3 beta -hydroxyste roid dehydrogenase/(5-4)-isomerase inhibitor cyproterone acetate on androge n metabolism were investigated. Androgen receptor mRNA was detected in SZ95 sebocytes and HaCaT keratinocytes but not in MeWo melanoma cells, whereas 3 beta -hydroxysteroid dehydrogenase/Delta (5-4)-isomerase isotype 1 mRNA a nd metabolic activity were only found in SZ95 sebocytes, The enzyme activit y could be inhibited by cyproterone acetate, Type 2 17 beta -hydroxysteroid dehydrogenase, type 1 5 alpha -reductase, and 3 alpha -hydroxysteroid dehy drogenase mRNA were expressed in all three cell populations tested, whereas type 3 17 beta -hydroxysteroid dehydrogenase mRNA could only be detected i n SZ95 sebocytes, The major metabolic steps of testosterone in SZ95 sebocyt es, primary sebocyte cultures, and HaCaT keratinocytes were its conversion to androstenedione by 17 beta -hydroxysteroid dehydrogenase and further to 5 alpha -androstanedione by 5 alpha -reductase. The type 1 5 alpha -reducta se selective inhibitor 4,7 beta -dimethyl-4-aza-5 alpha -cholestan-3-one, b ut not the type 2 selective inhibitor dihydrofinasteride, inhibited 5 alpha -reductase at low concentrations in SZ95 sebocytes and HaCaT keratinocytes , 5 alpha -androstanedione was degraded to androsterone by 3 alpha -hydroxy steroid dehydrogenase, which exhibited a stronger activity in HaCaT keratin ocytes than in SZ95 sebocytes and in primary sebocyte cultures. Lower level s of 5 alpha -dihydrotestosterone and 5 alpha -androstanediol were also det ected in all cells tested. Our investigations show that specific enzyme exp ression and activity in cultured sebocytes and keratinocytes seem to alloca te different duties to these cells in vitro. Sebocytes are able to synthesi ze testosterone from adrenal precursors and to inactivate it in order to ma intain androgen homeostasis, whereas keratinocytes are responsible for andr ogen degradation.