Steroid metabolism as a mechanism of escape from progesterone-mediated growth inhibition in Trichophyton mentagrophytes.
It has been shown by us and others that progesterone inhibits the growth of Trichophyton mentagrophytes and that the organism escapes from this inhibition over time. We report here studies which show that escape from growth inhibition is related to the enzymatic transformation of progesterone to polar metabolites. Isolation and identification of the progesterone metabolites confirm the production of 15 alpha-hydroxyprogesterone. In addition, three other metabolites were isolated. Two of these were determined to be 1-dehydroprogesterone and 11 alpha-hydroxyprogesterone. The third metabolite was a 1-dehydro-hydroxyprogesterone, but the location of the hydroxyl group could not be determined unequivocally. Studies using authentic 15 alpha-hydroxyprogesterone, 1-dehydroprogesterone, and 11 alpha-hydroxyprogesterone reveal that these derivatives are significantly less inhibitory to the growth of T. mentagrophytes than progesterone. Pretreatment of organisms with progesterone augments the rate of metabolism and enhances escape. We have described previously a progesterone-binding protein (PBP) in cytoplasmic extracts of T. mentagrophytes and hypothesized that progesterone mediates growth inhibition by binding to the PBP of this organism. The relative binding affinity that progesterone and its metabolites display for PBP correlates with the relative growth inhibitory potency of these compounds. These results suggest that metabolism of progesterone to more polar and less inhibitory compounds, which exhibit lower affinity for PBP, is the mechanism of escape from progesterone-mediated inhibition of growth in this organism.
Clemons
K V
KV
Department of Medicine, Stanford University School of Medicine, California 94305.
Stover
E P
EP
Schär
G
G
Stathis
P A
PA
Chan
K
K
Tökès
L
L
Stevens
D A
DA
Feldman
D
D
D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D006908:Hydroxyprogesterones / Q000378:metabolism / Q000494:pharmacology; D007700:Kinetics; D013058:Mass Spectrometry; D011374:Progesterone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D011376:Progesterone-Binding Globulin / Q000378:metabolism; D014249:Trichophyton / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism
D006908:Hydroxyprogesterones; D011376:Progesterone-Binding Globulin; C038897:1-dehydroprogesterone; C030228:11-hydroxyprogesterone; D011374:Progesterone; C044666:15-hydroxyprogesterone