Effects of dexamethasone on the levels of adrenal steroidogenic enzyme mRNA in rats treated with 4-aminopyrazolopyrimidine.
Following three 24 hourly serial injections of 4-aminopyrazolo[3,4-d]pyrimidine (4-APP) to rats, the levels of plasma corticotropin (ACTH) and of adrenal HMG-CoA reductase, the cholesterol side chain cleavage system, 3 beta-hydroxysteroid dehydrogenase, 21-hydroxylase, and adrenodoxin increased after an initial lag of 17 h. In contrast the mRNA level of 11 beta-hydroxylase was differently regulated since it was elevated after 17 and 24 h and decreased thereafter to basal values. These increases appear to be related to ACTH secretion since they were blocked by the coadministration of dexamethasone (Dex) and 4-APP. Also 3 h after the administration of Dex to 4-APP treated rats rapid decreases in plasma corticosterone and ACTH levels were accompanied by decreases in mRNA levels of HMG-CoA reductase and low density lipoprotein receptor, two components involved in the synthesis and transport of cholesterol. The mRNA level of the electron donor adrenodoxin was also decreased, suggesting that this component participates in the short term regulation of corticosterone synthesis in the rat adrenal. The adrenal response was more readily observed with components involved in the steps preceding cholesterol biosynthesis than in those subsequent to cholesterol in the corticosteroid pathway. However, the effects of 4-APP on the latter pathway were well documented with mRNA analysis performed by Northern blot, a more sensitive technique than the Western blot used for protein quantification. The entire metabolism of the corticosterone biosynthetic pathway was thus affected in rats treated with 4-APP. Taken collectively these results indicate that under acute lipoprotein depletion rat adrenals developed a compensatory mechanism enabling them to synthesize and utilize cholesterol for corticosteroid synthesis.
Department of Biochemistry, Faculty of Medicine, University of Sherbrooke, QC, Canada.
J G
JG
Lehoux
L
L
Ducharme
D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis* / Q000235:genetics; D000302:Adrenal Cortex / Q000187:drug effects* / Q000201:enzymology; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis / Q000097:blood; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000325:Adrenodoxin / Q000096:biosynthesis / Q000235:genetics; D000450:Aldosterone / Q000097:blood; D000616:Aminoglutethimide / Q000494:pharmacology; D000818:Animals; D001386:Azides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000096:biosynthesis / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013252:Steroid 11-beta-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D013255:Steroid 21-Hydroxylase / Q000096:biosynthesis / Q000235:genetics
D000305:Adrenal Cortex Hormones; D001386:Azides; D012333:RNA, Messenger; D000616:Aminoglutethimide; D000325:Adrenodoxin; C065795:4-azidophenylpropionamide; D000450:Aldosterone; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D015096:3-Hydroxysteroid Dehydrogenases; D006903:Hydroxymethylglutaryl CoA Reductases; D013255:Steroid 21-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme