Pharmacological Effects of Propylthiouracil on Corticosterone Secretion in Male Rats

Background: We investigated the direct effects of propylthiouracil (PTU) on corticosterone secretion both in vivo and in vitro. Methods: Male rats were divided into 4 groups and then injected subcutaneously with saline, PTU, PTU plus thyroxine (T₄), or T₄ once daily for 2 weeks. After 2 weeks, rats were decapitated or received adrenocorticotropic hormone (ACTH), intravenously. Zona fasciculata-reticularis (ZFR) cells from normal, saline-, PTU-, PTU plus T₄-, or T₄-treated rats were incubated with ACTH, forskolin, 8-Br-cAMP, deoxycorticosterone (DOC) ± PTU (1, 2, or 5 mg/mL) at 37°C for 2 hours. Corticosterone concentrations in plasma and cell media, and 3′:5′-cyclic adenosine monophosphate (cAMP) production in ZFR cells were determined by radioimmunoassay. The effects of PTU on the activities of steroidogenic enzymes in ZFR cells were measured by the amounts of intermediate steroidal products separated by thin-layer chromatography. Results: The basal and ACTH-stimulated levels of plasma corticosterone in PTU-treated rats were lower as compared to saline-treated animals. Both basal and ACTH-stimulated corticosterone secretion were inhibited by PTU > 2 mg/mL in rat ZFR cells. The cAMP production induced by forskolin was lower in PTU, PTU plus T_4, or T₄-treated rats than in saline-treated animals. Chronic administration of PTU or PTU plus T₄ inhibited the 3β-hydroxysteroid dehydrogenase, 21β-hydroxylase, and 11β-hydroxylase activities. Administration of PTU (1, 2, and 5 mg/mL) suppressed the basal, ACTH, 8-Br-cAMP, forskolin, and DOC-stimulated corticosterone secretion in rat ZFR cells. Likewise, PTU > 2 mg/mL inhibited the ACTH and 8-Br-cAMP-stimulated levels of intracellular cAMP in rat ZFR cells. Conclusions: These results suggest that PTU counteracts both basal and ACTH-induced adrenal steroidogenesis through their attenuation of the activity of 11β-hydroxylase and cAMP production in rat ZFR cells.