Downregulation of CYP2D16 by ACTH in the guinea pig adrenal cortex: time course, reversibility, and mechanism of action.
Studies were done to investigate the actions of ACTH on the expression of CYP2D16 in the guinea pig adrenal cortex. Guinea pigs were treated with ACTH for 1, 3, or 7 days. In addition, some animals received ACTH for 7 days and were then untreated for an additional 3 or 7 days to test for reversibility of ACTH actions. ACTH treatment caused a time-dependent decrease in the rates of adrenal microsomal bufuralol metabolism, a CYP2D-catalyzed reaction; hepatic bufuralol metabolism was unaffected by ACTH. Adrenal enzyme activity was significantly reduced by ACTH within 1 day and decreased by 80% after 7 days. Western blotting and in situ hybridization analyses revealed corresponding declines in adrenal CYP2D16 protein and mRNA concentrations. Nuclear runoff assays indicated that ACTH treatment inhibited CYP2D16 expression at the transcriptional level. Adrenal 17 alpha-hydroxylase activities were increased by ACTH treatment, but CYP17 protein concentrations were not affected. Following cessation of ACTH administration, the rates of adrenal bufuralol metabolism and CYP2D16 protein and mRNA concentrations returned to control levels within 7 days. The results demonstrate that ACTH has a relatively rapid and reversible effect to inhibit adrenal CYP2D16 transcription, thereby decreasing adrenal xenobiotic metabolism. Thus, the actions of ACTH on CYP2D16 expression are opposite to those on other adrenal p450 isozymes, indicating unique regulatory mechanisms.
Colby
Howard D
HD
Department of Basic and Pharmaceutical Sciences, Albany College of Pharmacy, Albany, NY 12208, USA. colbyh@acp.edu
Longhurst
Penelope A
PA
Burczynski
Joseph M
JM
Hayes
Jill R
JR
Yuan
Bing-Bing
BB
Voigt
Jeffrey V
JV
D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004983:Ethanolamines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006168:Guinea Pigs; D017403:In Situ Hybridization; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D013997:Time Factors
D004983:Ethanolamines; D012333:RNA, Messenger; C010831:bufuralol; D000324:Adrenocorticotropic Hormone; D001189:Aryl Hydrocarbon Hydroxylases; C118568:cytochrome P-450 CYP2D16 (guinea pig)