Greater conversion of testosterone to 5 alpha-dihydrotestosterone, reflecting increased peripheral 5 alpha-reductase activity in nude mice treated with high doses of cyclosporine A.
Following cyclosporine A (CsA) immunosuppressive therapy in kidney grafts, increased body hair growth (hypertrichosis and/or hirsutism) without significant variation in normal circulating plasma androgen levels (as observed in idiopathic hirsutism) has been reported by several authors. Other authors have described increased hair growth in nude mice treated with CsA. In order to evaluate the action of this drug in target tissues, using dorsal skin homogenates from nude mice treated with various doses of CsA, we measured the metabolic conversion of testosterone (T) to its 5 alpha-reduced products, reflecting 5 alpha-reductase activity (5 alpha-RA). Three groups of 5 female nude mice were treated with an oral suspension containing CsA 5 mg/kg (group 1), 25 mg/kg (group 2) and 100 mg/kg (group 3), respectively, and the results, including 5 alpha-DHT and Adiol formation, were compared with those obtained in a control group (n = 5) receiving only the olive oil vehicle. Cutaneous metabolic conversion of T was determined using tritiated T as substrate. After 1 h of incubation, 5 alpha-DHT and other 5 alpha-reduced products formed were separated and quantified using a reverse-phase chromatography column fitted to a flow-through radioactivity detector. Mean +/- SD 5 alpha-DHT formation (expressed as pmol per 100 mg of protein per h) was found to be increased in the treated groups (group 1: 3.17 +/- 0.37, group 2: 3.10 +/- 0.13, group 3: 4.26 +/- 0.20), respectively 7.5% (NS), 5.10% (NS) and 44.4% (P = 0.01) higher than in the control group (2.95 +/- 0.13). In addition to 5 alpha-DHT, enhanced formation of delta 4-androstenedione (delta 4), 5 alpha-androstan-3 beta,17 beta-diol (3 beta-diol) and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) were also observed in the treated groups. These results show a significantly increased formation of 5 alpha-DHT (and Adiol) in nude mice treated with high dose-levels of CsA.
Boudou
P
P
Hormone Biology Laboratory, Hôpital Saint-Louis, Paris, France.
Fiet
J
J
Vexiau
P
P
Villette
J M
JM
Hardy
N
N
Dreux
C
C
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D003524:Cyclosporins / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008819:Mice, Nude; D012867:Skin / Q000201:enzymology* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*
D003524:Cyclosporins; D013196:Dihydrotestosterone; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase