Glucocorticoid and mineralocorticoid pathways in two adrenocortical carcinomas: comparison of the effects of o,p'-dichlorodiphenyldichloroethane, aminoglutethimide and 2-p-aminophenyl-2-phenylethylamine in vitro.
The synthesis of glucocorticoids and mineralocorticoids in vitro was studied in an adrenocortical carcinoma after alblation from an 11.5-year-old boy. This patient had been unsuccessfully treated with high doses of o,p'-dichlorodiphenyldichloroethane (o,p'-DDD) and aminoglutethimide. These in-vitro results were compared with those obtained with another adrenocortical carcinoma removed from a 26-year-old woman who had received no preoperative treatment. The sensitivity of these adrenocortical carcinomas to o,p'-DDD, aminoglutethimide and 2-(p-aminophenyl)-2-phenylethylamine (SKF 12185) was investigated. Synthesis of cortisol (47%) and corticosterone (45%) in control incubations showed that 11 beta-hydroxylase activity was not affected by the treatment. This explains the raised level of plasma cortisol in the treated child. All three compounds inhibited both 11 beta-hydroxylase and 18-hydroxylase activities up to 95%, depending on the inhibitor. This study shows (a) an inhibitory effect of o,p'-DDD on the steroidogenesis of an adrenocortical carcinoma in vitro, an effect not previously reported in man or laboratory animals, and (b) the in-vitro efficacy of o,p-DDD and aminoglutethimide on corticosteroidogenesis by a carcinoma unresponsive to treatment in vivo. This discrepancy between data obtained in vivo and in vitro could possibly be explained by either an insufficient ratio of ingested dose: tumour mass, or a malabsorption of the drugs in this patient.
D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000328:Adult; D000616:Aminoglutethimide / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology; D002648:Child; D003350:Cortodoxone / Q000378:metabolism; D003900:Desoxycorticosterone / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000096:biosynthesis*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008901:Mineralocorticoids / Q000096:biosynthesis*; D008939:Mitotane / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors
D000814:Aniline Compounds; D005938:Glucocorticoids; D008901:Mineralocorticoids; D010627:Phenethylamines; D000616:Aminoglutethimide; D003900:Desoxycorticosterone; C006221:2-(4-aminophenyl)-2-phenethylamine; D008939:Mitotane; D013250:Steroid Hydroxylases; D003350:Cortodoxone