Kinetic evidence for a unique testosterone-receptor complex in 5 alpha-reductase sufficient genital skin fibroblasts and the effects of 5 alpha-reductase deficiency on its formation.
When 5 alpha-reductase-sufficient genital skin fibroblast (GSF) monolayers are incubated with testosterone (T), they first form androgen (A)-receptor (R) complexes that dissociate at a fast rate [k(37 degrees C = 0.024 min-1]. As T is converted to 5 alpha-dihydrotestosterone (DHT), this population of T-R complexes is eventually replaced by one that dissociates much more slowly [k(37 degrees C) = 0.006 min-1], at a rate typical of DHT-R complexes. During the course of T to DHT conversion, one may observe a population of A-R complexes that has a linear (monophasic) intermediate dissociation rate constant [k(37 degrees C) = 0.012 min-1]; this population cannot simply reflect a mixture of T- and DHT-R complexes. The rate at which the complexes are processed from one dissociative form to the next varies with the incubation temperature and the presence or absence of serum in the medium; it also varies within and among GSF strains under apparently constant conditions. To explain these facts, we propose a model that enables the 5 alpha-reductase enzyme to influence the processive dissociative behaviour of T-R complexes by engaging in some sort of coupling with the AR. The proposal is strengthened by a set of observations in cells with constitutive, mendelian or inhibitor-induced 5 alpha-reductase deficiency that preclude a simple quantitative relation between A-R complex processing and the extent of T to DHT conversion.
Cell Genetics Laboratory, Lady Davis Institute for Medical Research, McGill University, Montreal, Canada.
M
M
Kaufman
L
L
Pinsky
M
M
Trifiro
R
R
Lumbroso
N
N
Sabbaghian
B
B
Gottlieb
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000172:deficiency / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D001769:Blood; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D005835:Genitalia / Q000166:cytology / Q000201:enzymology*; D006358:Hot Temperature; D006801:Humans; D007700:Kinetics; D008297:Male; D011944:Receptors, Androgen / Q000378:metabolism*; D012867:Skin / Q000201:enzymology; D013256:Steroids / Q000494:pharmacology; D013739:Testosterone / Q000378:metabolism*
D058891:5-alpha Reductase Inhibitors; D011944:Receptors, Androgen; D013256:Steroids; D013196:Dihydrotestosterone; D013739:Testosterone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase