RESUMEN
Lanthanum (La+++) is a well-known Ca++ antagonist in a number of biological systems. It was used in the present study to examine the role of Ca++ in the regulation of adenyl cyclase of the adrenal cortex by ACTH. In micromolar concentrations, .La+++ inhibited both cyclic AMP and corticosterone response of isolated adrenal cortex cells to ACTH. However, a number of intracellular processes were not affected by La+++. These include the stimulation of steroidogenesis by dibutyryl cyclic AMP, conversion of several steroid precursors into corticosterone, and stimulation of the latter by glucose. Thus, inhibition of steroidogenesis by La+++ appears to be solely due to an inhibition of ACTH-stimulated cyclic AMP formation. Electron microscope examination showed that La+++ was localized on plasma membrane of the cells and did not appear to penetrate beyond this region. Since La+++ is believed to replace Ca++ at superficial binding sites on the cell membrane, it is proposed that Ca++ at these sites plays an important role in the regulation of adenyl cyclase by ACTH. Similarities in the role of Ca++ in "excitation-contraction" coupling and in the ACTH-adenyl cyclase system raise the possibility that a contractile protein may be involved in the regulation of adenyl cyclase by those hormones which are known to require Ca++ in the process.
Asunto(s)
Corteza Suprarrenal/metabolismo , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/farmacología , Corticosterona/biosíntesis , AMP Cíclico/biosíntesis , Lantano/farmacología , Corteza Suprarrenal/efectos de los fármacos , Corteza Suprarrenal/ultraestructura , Animales , Bucladesina/farmacología , Calcio/farmacología , Desoxicorticosterona/metabolismo , Relación Dosis-Respuesta a Droga , Hidroxiprogesteronas/metabolismo , Técnicas In Vitro , Cinética , Microscopía Electrónica , Modelos Biológicos , Pregnenolona/metabolismo , RatasAsunto(s)
Neoplasias de las Glándulas Suprarrenales/metabolismo , Desoxicorticosterona/metabolismo , Mitocondrias/metabolismo , Glándulas Suprarrenales/metabolismo , Amobarbital/farmacología , Animales , Sistema Libre de Células , Corticosterona/biosíntesis , Cianuros/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Citosol/enzimología , Flavoproteínas , Fructosa , Glicerofosfatos/metabolismo , Hidroxilación , Isocitrato Deshidrogenasa/metabolismo , Malato Deshidrogenasa/metabolismo , NAD/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , NADP/metabolismo , Neoplasias Experimentales/metabolismo , Consumo de Oxígeno , Piruvatos/metabolismo , Ratas , Rotenona/farmacología , Succinatos/metabolismoRESUMEN
Electron microscope studies were carried out with the adrenocortical carcinoma 494 and normal adrenal cortex tissue. The mitochondria of the tumor cells showed marked differences when compared with mitochondria from fasciculata cells of the normal adrenal cortex. These differences were primarily related to mitochondrial number and crista structure. Corticosterone production in isolated tumor cells was extremely low and neither ACTH nor dibutyryl cyclic AMP had any stimulatory effect. Normal adrenal cells showed at least a tenfold increase under identical conditions. In the presence of corticosteroid precursors the amount of corticosterone produced by the tumor cells was much less than that produced by normal cells. The results indicate a reduced capacity for 11beta-hydroxylation in the tumor mitochondria and a possible reduced capacity for biosynthetic steps before the 11beta-hydroxylation reaction. Glycolysis in isolated tumor cells was also lower than in normal cells. Isolated tumor mitochondria oxidized succinate normally with a good degree of coupling with phosphorylation. However, unlike normal adrenal mitochondria, the tumor mitochondria showed little or no oxygen uptake with other Krebs cycle substrates. These data suggest that the tumor mitochondria may be lacking in the flavoprotein dehydrogenases responsible for the oxidation of NADH and NADPH, although other components of the respiratory chain may be intact.