Regulation of hepatic steroid receptors and enzymes by the 3beta-hydroxysteroid dehydrogenase inhibitor trilostane.
Therapies designed to treat hypercortisolism have usually sought to reduce circulating glucocorticoid concentrations, however the local tissue endocrine environment could be an alternative target. The 3beta-hydroxysteroid dehydrogenase Delta5-4 isomerase (3beta-HSD) inhibitor trilostane is of interest, since, although it is only moderately and transiently effective in reducing circulating steroid, it is remarkably effective in alleviating Cushing's symptoms in veterinary applications. To seek alternative modes of action, male Wistar rats were treated with trilostane. Although final circulating corticosteroid concentrations were unaffected, liver 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) transcription and translation was significantly increased, whereas 3beta-HSD was not affected either in liver or adrenal. Glucocorticoid receptor (GR) mRNA was down-regulated, and mineralocorticoid receptor (MR) up-regulated by trilostane treatment: no changes in 11beta-HSD1 mRNA were observed. Trilostane also had no direct effect on GR response element-mediated gene transcription. The results show that the tissue endocrine environment is affected by trilostane treatment in the absence of sustained changes in circulating corticosteroid. The combination of increased 11beta-HSD2 and reduced GR expression in target organs could be expected to ameliorate the effects of excess glucocorticoid, suggesting new therapeutic approaches.
Malouitre
S D M
SD
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK.
Barker
S
S
Puddefoot
J R
JR
Jalili
J
J
Glover
H R
HR
Vinson
G P
GP
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics* / Q000378:metabolism; D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000097:blood; D000818:Animals; D002460:Cell Line; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection
D000305:Adrenal Cortex Hormones; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D013196:Dihydrotestosterone; D015067:17-Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; C009954:trilostane