Effects of cyclosporine-A on steroid secretion of dispersed rat adrenocortical cells.
The acute effect of cyclosporine-A (CSA), a potent immunosuppressive agent, on the secretory activity of dispersed rat adrenocortical cells was investigated. The production of the following steroid hormones was assayed by high performance liquid chromatography: pregnenolone (PREG), progesterone (PROG), 11-deoxycorticosterone (DOC), corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18OH-DOC), 18-hydroxycorticosterone (18OH-B) and aldosterone (ALDO); B and ALDO outputs were also measured by radioimmunoassay. Low concentrations of CSA (0.1-0.2 mg/ml) enhanced basal, but not ACTH- or angiotensin-II (ANG-II) 10(-8) M-stimulated, secretions of PREG, non-18-hydroxylated steroids (PROG, DOC and B) and 18-hydroxylated steroids (18OH-DOC, 18OH-B and ALDO) of both zona glomerulosa (ZG) and zonae fasciculata and reticularis (ZF/ZR) cells. Middle concentrations of CSA (from 0.3 to 0.5 mg/ml) did not affect PREG yield, nor did they alter basal and ACTH-stimulated post-PREG output of both ZG and ZF/ZR cells; however, they elicited a marked decrease in ANG-II-enhanced production of 18-hydroxylated steroid by AG cells. Concentrations of CSA higher than 0.5 mg/ml strikingly reduced either basal and agonist-stimulated over-all steroidogenesis of both ZG and ZF/ZR cells. These findings suggest that CSA at low concentrations strongly stimulates the conversion of cholesterol to PREG (i.e. the rate-limiting step of steroidogenesis), while at middle concentrations it did not affect this early step, but specifically interferes with the intracellular events which transduce the stimulatory signal of ANG-II on the late steps of mineralocorticoid production (i.e. the conversion of B to ALDO). At higher concentrations, CSA probably exerts a cytotoxic effect.
Mazzocchi
G
G
Department of Anatomy, University of Padua, Italy.
Markowska
A
A
Andreis
P G
PG
Tortorella
C
C
Neri
G
G
Gottardo
G
G
Malendowicz
L K
LK
Nussdorfer
G G
GG
D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000502:physiology; D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar
D000305:Adrenal Cortex Hormones; D000804:Angiotensin II; D016572:Cyclosporine; D000324:Adrenocorticotropic Hormone