Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment.
Autoregulation of glucocorticoid receptor (GR) concentration in vivo may be an important determinant of steroid sensitivity. The dynamics of GR regulation were assessed and compared to regulation of tyrosine aminotransferase (TAT) expression in liver tissue taken from rats treated with a single 50 mg/kg i.v. dose of methylprednisolone. Plasma methylprednisolone concentrations were determined by HPLC analysis. Receptor and TAT message levels were determined by quantitative Northern hybridization. Methylprednisolone plasma kinetics showed a half-life of 0.6 h. Receptor occupancy occurred rapidly and cytosolic GR reappeared over 2-12 h. TAT activity rose between 2 and 6 h and then dissipated. Reduction in receptor mRNA levels occurred very rapidly, being detectable by 30 min following steroid administration. A down-regulated steady-state in GR message expression was reached by 2 h post-injection, and was maintained throughout the 18 h examined in this study. Comparison of methylprednisolone kinetics demonstrated that down-regulation was maintained long after drug was eliminated. In contrast, TAT message induction occurred with a sharp peak; maximal induction occurred between 5-6 h and return to baseline at approx. 8-10 h post-induction. This study shows that unlike TAT induction, GR message repression in vivo does not require continual presence of hormone.
DuBois
D C
DC
Department of Biological Sciences, School of Pharmacy, State University of New York at Buffalo 14260, USA.
Xu
Z X
ZX
McKay
L
L
Almon
R R
RR
Pyszcznski
N
N
Jusko
W J
WJ
D000315:Adrenalectomy; D000818:Animals; D015536:Down-Regulation; D004790:Enzyme Induction / Q000187:drug effects; D005938:Glucocorticoids / Q000097:blood / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008775:Methylprednisolone / Q000097:blood / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014444:Tyrosine Transaminase / Q000096:biosynthesis*
D005938:Glucocorticoids; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014444:Tyrosine Transaminase; D008775:Methylprednisolone