Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment. 1995

D C DuBois, and Z X Xu, and L McKay, and R R Almon, and N Pyszcznski, and W J Jusko
Department of Biological Sciences, School of Pharmacy, State University of New York at Buffalo 14260, USA.

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.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008775 Methylprednisolone A PREDNISOLONE derivative with similar anti-inflammatory action. 6-Methylprednisolone,Medrol,Metipred,Urbason,6 Methylprednisolone
D011965 Receptors, Glucocorticoid Cytoplasmic proteins that specifically bind glucocorticoids and mediate their cellular effects. The glucocorticoid receptor-glucocorticoid complex acts in the nucleus to induce transcription of DNA. Glucocorticoids were named for their actions on blood glucose concentration, but they have equally important effects on protein and fat metabolism. Cortisol is the most important example. Corticoid Type II Receptor,Glucocorticoid Receptors,Glucocorticoids Receptor,Corticoid II Receptor,Corticoid Type II Receptors,Glucocorticoid Receptor,Receptors, Corticoid II,Receptors, Corticoid Type II,Receptors, Glucocorticoids,Corticoid II Receptors,Glucocorticoids Receptors,Receptor, Corticoid II,Receptor, Glucocorticoid,Receptor, Glucocorticoids
D004790 Enzyme Induction An increase in the rate of synthesis of an enzyme due to the presence of an inducer which acts to derepress the gene responsible for enzyme synthesis. Induction, Enzyme
D005938 Glucocorticoids A group of CORTICOSTEROIDS that affect carbohydrate metabolism (GLUCONEOGENESIS, liver glycogen deposition, elevation of BLOOD SUGAR), inhibit ADRENOCORTICOTROPIC HORMONE secretion, and possess pronounced anti-inflammatory activity. They also play a role in fat and protein metabolism, maintenance of arterial blood pressure, alteration of the connective tissue response to injury, reduction in the number of circulating lymphocytes, and functioning of the central nervous system. Glucocorticoid,Glucocorticoid Effect,Glucorticoid Effects,Effect, Glucocorticoid,Effects, Glucorticoid
D000315 Adrenalectomy Excision of one or both adrenal glands. (From Dorland, 28th ed) Adrenalectomies
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012333 RNA, Messenger RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm. Messenger RNA,Messenger RNA, Polyadenylated,Poly(A) Tail,Poly(A)+ RNA,Poly(A)+ mRNA,RNA, Messenger, Polyadenylated,RNA, Polyadenylated,mRNA,mRNA, Non-Polyadenylated,mRNA, Polyadenylated,Non-Polyadenylated mRNA,Poly(A) RNA,Polyadenylated mRNA,Non Polyadenylated mRNA,Polyadenylated Messenger RNA,Polyadenylated RNA,RNA, Polyadenylated Messenger,mRNA, Non Polyadenylated
D014444 Tyrosine Transaminase An enzyme that catalyzes the conversion of L-TYROSINE and 2-oxoglutarate to 4-hydroxyphenylpyruvate and L-GLUTAMATE. It is a pyridoxal-phosphate protein. L-PHENYLALANINE is hydroxylated to L-tyrosine. The mitochondrial enzyme may be identical with ASPARTATE AMINOTRANSFERASES (EC 2.6.1.1.). Deficiency of this enzyme may cause type II Tyrosinemia (see TYROSINEMIAS). EC 2.6.1.5. Tyrosine Aminotransferase,Aminotransferase, Tyrosine,Transaminase, Tyrosine

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