scholarly journals The Selective NMDA Receptor GluN2B Subunit Antagonist CP-101,606 with Antidepressant Properties Modulates Cytochrome P450 Expression in the Liver

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1643
Author(s):  
Ewa Bromek ◽  
Anna Haduch ◽  
Marta Rysz ◽  
Joanna Jastrzębska ◽  
Renata Pukło ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cytochrome P450 ◽  
Nmda Receptor ◽  
Depressive Disorders ◽  
Mrna Level ◽  
Mrna Levels ◽  
Serum Growth Hormone ◽  
Control Value ◽  
Serum Hormone ◽  
Major Depressive Disorders

Recent research indicates that selective NMDA receptor GluN2B subunit antagonists may become useful for the treatment of major depressive disorders. We aimed to examine in parallel the effect of the selective NMDA receptor GluN2B subunit antagonist CP-101,606 on the pituitary/serum hormone levels and on the regulation of cytochrome P450 in rat liver. CP-101,606 (20 mg/kg ip. for 5 days) decreased the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A, but not that of CYP2C6. The alterations in enzymatic activity were accompanied by changes in the CYP protein and mRNA levels. In parallel, a decrease in the pituitary growth hormone-releasing hormone, and in serum growth hormone and corticosterone (but not T3 and T4) concentration was observed. After a 3-week administration period of CP-101,606 less changes were found. A decrease in the CYP3A enzyme activity and protein level was still maintained, though no change in the mRNA level was found. A slight decrease in the serum concentration of corticosterone was also maintained, while GH level returned to the control value. The obtained results imply engagement of the glutamatergic system in the neuroendocrine regulation of cytochrome P450 and potential involvement of drugs acting on NMDA receptors in metabolic drug–drug interactions.

Glucocorticoids increase sodium pump α2- and β1-subunit abundance and mRNA in rat skeletal muscle

2001 ◽  
Vol 280 (3) ◽  
pp. C509-C516 ◽  
Author(s):  
Curtis B. Thompson ◽  
Inge Dorup ◽  
Julie Ahn ◽  
Patrick K. K. Leong ◽  
Alicia A. McDonough
Keyword(s):  
Sodium Pump ◽  
Mrna Level ◽  
Chronic Obstructive Lung Disease ◽  
Specific Pattern ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Ouabain Binding ◽  
Adrenal Steroid ◽  
Control Value ◽  
Hindlimb Muscle

Fourteen-day adrenal steroid treatment increases [3H]ouabain binding sites 22–48% in muscle biopsies from patients treated with adrenal steroids for chronic obstructive lung disease and in rats treated with dexamethasone (Dex). Ouabain binding measures plasma membrane sodium pumps (Na+-K+-ATPase) with isoform-dependent affinity. In this study we have established the specific pattern of Dex regulation of sodium pump isoform protein and mRNA levels in muscle. Rats were infused with Dex (0.1 mg/kg per day) or vehicle for 14 days. Abundance of sodium pump catalytic α1- and α2-subunits and glycoprotein β1- and β2-subunits was determined by immunoblot in soleus, extensor digitorum longus, whole gastrocnemius, and diaphragm and was normalized to the mean vehicle control value. Dex increased α2 and β1 protein in all muscle types by 53–78% and ∼50%, respectively. Dex increased α1protein only in diaphragm (65 ± 7%). At the mRNA level in whole hindlimb muscle, Dex increased α2 (6.4 ± 0.5-fold) and β1 (1.54 ± 0.15-fold) and decreased β2 (to 0.36 ± 0.6 of control). In summary, α2β1 is the Dex-responsive pump in all skeletal muscles, and changes in α2 and β1mRNA levels can drive the 50% change in α2β1-subunits, which can account for the reported increase in [3H]ouabain binding.

scholarly journals Metabolic hormones regulate basal and growth hormone-dependent igf2 mRNA level in primary cultured coho salmon hepatocytes: effects of insulin, glucagon, dexamethasone, and triiodothyronine

2009 ◽  
Vol 204 (3) ◽  
pp. 331-339 ◽  
Author(s):  
A L Pierce ◽  
J T Dickey ◽  
L Felli ◽  
P Swanson ◽  
W W Dickhoff
Keyword(s):  
Growth Hormone ◽  
Coho Salmon ◽  
Mrna Level ◽  
Postnatal Growth ◽  
Mrna Levels ◽  
Growth Physiology ◽  
Metabolic Hormones ◽  
Synergistic Regulation ◽  
Growth Promoting ◽  
Stimulation Of

Igf1 and Igf2 stimulate growth and development of vertebrates. Circulating Igfs are produced by the liver. In mammals, Igf1 mediates the postnatal growth-promoting effects of growth hormone (Gh), whereas Igf2 stimulates fetal and placental growth. Hepatic Igf2 production is not regulated by Gh in mammals. Little is known about the regulation of hepatic Igf2 production in nonmammalian vertebrates. We examined the regulation of igf2 mRNA level by metabolic hormones in primary cultured coho salmon hepatocytes. Gh, insulin, the glucocorticoid agonist dexamethasone (Dex), and glucagon increased igf2 mRNA levels, whereas triiodothyronine (T3) decreased igf2 mRNA levels. Gh stimulated igf2 mRNA at physiological concentrations (0.25×10−9 M and above). Insulin strongly enhanced Gh stimulation of igf2 at low physiological concentrations (10−11 M and above), and increased basal igf2 (10−8 M and above). Dex stimulated basal igf2 at concentrations comparable to those of stressed circulating cortisol (10−8 M and above). Glucagon stimulated basal and Gh-stimulated igf2 at supraphysiological concentrations (10−7 M and above), whereas T3 suppressed basal and Gh-stimulated igf2 at the single concentration tested (10−7 M). These results show that igf2 mRNA level is highly regulated in salmon hepatocytes, suggesting that liver-derived Igf2 plays a significant role in salmon growth physiology. The synergistic regulation of igf2 by insulin and Gh in salmon hepatocytes is similar to the regulation of hepatic Igf1 production in mammals.

Function-specific calcium stores selectively regulate growth hormone secretion, storage, and mRNA level

2002 ◽  
Vol 282 (4) ◽  
pp. E810-E819 ◽  
Author(s):  
James D. Johnson ◽  
Christian Klausen ◽  
Hamid R. Habibi ◽  
John P. Chang
Keyword(s):  
Growth Hormone ◽  
Secretory Pathway ◽  
Mrna Level ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Signal Amplitude ◽  
Calcium Stores ◽  
Mrna Levels ◽  
Intracellular Ca

Ca+ stores may regulate multiple components of the secretory pathway. We examined the roles of biochemically independent intracellular Ca2+stores on acute and long-term growth hormone (GH) release, storage, and mRNA levels in goldfish somatotropes. Thapsigargin-evoked intracellular Ca2+ concentration ([Ca2+]i) signal amplitude was similar to the Ca2+-mobilizing agonist gonadotropin-releasing hormone, but thapsigargin (2 μM) did not acutely increase GH release, suggesting uncoupling between [Ca2+]i and exocytosis. However, 2 μM thapsigargin affected long-term secretory function. Thapsigargin-treated cells displayed a steady secretion of GH (2, 12, and 24 h), which decreased GH content (12 and 24 h), but not GH mRNA/production (24 h). In contrast to the results with thapsigargin, activating the ryanodine (Ry) receptor (RyR) with 1 nM Ry transiently increased GH release (2 h). Prolonged activation of RyR (24 h) reduced GH release, contents and apparent production, without changing GH mRNA levels. Inhibiting RyR with 10 μM Ry increased GH mRNA levels, production, and storage (2 h). Increasing [Ca2+]i independently of Ca2+stores with the use of 30 mM KCl decreased GH mRNA. Collectively, these results suggest that parts of the secretory pathway can be controlled independently by function-specific Ca2+ stores.

scholarly journals Tissue-specific gene expression in mouse hepatocytes cultured in growth-restricting medium.

1988 ◽  
Vol 8 (8) ◽  
pp. 3338-3344 ◽  
Author(s):  
T Spiegelberg ◽  
J O Bishop
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Mrna Level ◽  
Alpha Fetoprotein ◽  
Apolipoprotein A1 ◽  
Specific Gene ◽  
Mrna Levels ◽  
Hormonal Stimulation ◽  
Tissue Specific

Culture conditions which maintain hepatocytes in their in vivo state are not known. This hampers the study of liver gene expression and of direct responses of liver genes to hormonal stimulation. We argued that hepatocytes that were unable to divide might retain in vivo characteristics. We therefore plated mouse (BALB/c) hepatocytes on plastic dishes in medium lacking arginine and measured the levels and transcription rates of six tissue-specific mRNAs over a period of days. Alpha-fetoprotein mRNA began to accumulate at about 48 h of culture, and transcription could sometimes be detected after 72 h. The levels and transcription rates of four mRNAs (albumin, alpha-1-antitrypsin, apolipoprotein A1, and major urinary protein [MUP]) fell sharply. The rate of transcription of transferrin mRNA fell less rapidly, and its level remained high, partly due to its longer half-life. The overall pattern of gene expression in the plated cells did not exactly parallel that of either fetal or regenerating liver. The hepatocytes remained responsive to hormonal stimulation. Insulin and dexamethasone each tended to counteract changes in mRNA levels, for example, preventing the accumulation of alpha-fetoprotein mRNA. The effects of insulin were primarily due to changes in transcription rates. Bovine growth hormone and thyroxine elevated the levels of most of the mRNAs. Many of the effects of these hormones, when added singly, could not be ascribed to changes in transcription. The level of MUP mRNA was strongly affected by added hormones. The mRNA level at 5 days was increased by added insulin, dexamethasone, growth hormone, and thyroxine. In the presence of these three hormones, the decay in the transcription rate of the MUP genes was reduced about 10-fold. We conclude that hepatocytes plated under these nongrowing conditions can provide insights into the hormonal responsiveness of tissue-specific genes.

Tissue-specific gene expression in mouse hepatocytes cultured in growth-restricting medium

1988 ◽  
Vol 8 (8) ◽  
pp. 3338-3344
Author(s):  
T Spiegelberg ◽  
J O Bishop
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Mrna Level ◽  
Alpha Fetoprotein ◽  
Apolipoprotein A1 ◽  
Specific Gene ◽  
Mrna Levels ◽  
Hormonal Stimulation ◽  
Tissue Specific

Culture conditions which maintain hepatocytes in their in vivo state are not known. This hampers the study of liver gene expression and of direct responses of liver genes to hormonal stimulation. We argued that hepatocytes that were unable to divide might retain in vivo characteristics. We therefore plated mouse (BALB/c) hepatocytes on plastic dishes in medium lacking arginine and measured the levels and transcription rates of six tissue-specific mRNAs over a period of days. Alpha-fetoprotein mRNA began to accumulate at about 48 h of culture, and transcription could sometimes be detected after 72 h. The levels and transcription rates of four mRNAs (albumin, alpha-1-antitrypsin, apolipoprotein A1, and major urinary protein [MUP]) fell sharply. The rate of transcription of transferrin mRNA fell less rapidly, and its level remained high, partly due to its longer half-life. The overall pattern of gene expression in the plated cells did not exactly parallel that of either fetal or regenerating liver. The hepatocytes remained responsive to hormonal stimulation. Insulin and dexamethasone each tended to counteract changes in mRNA levels, for example, preventing the accumulation of alpha-fetoprotein mRNA. The effects of insulin were primarily due to changes in transcription rates. Bovine growth hormone and thyroxine elevated the levels of most of the mRNAs. Many of the effects of these hormones, when added singly, could not be ascribed to changes in transcription. The level of MUP mRNA was strongly affected by added hormones. The mRNA level at 5 days was increased by added insulin, dexamethasone, growth hormone, and thyroxine. In the presence of these three hormones, the decay in the transcription rate of the MUP genes was reduced about 10-fold. We conclude that hepatocytes plated under these nongrowing conditions can provide insights into the hormonal responsiveness of tissue-specific genes.

scholarly journals Hormonal regulation of the zonated expression of cytochrome P-450 3A in rat liver

1995 ◽  
Vol 309 (1) ◽  
pp. 55-61 ◽  
Author(s):  
T Oinonen ◽  
K O Lindros
Keyword(s):  
Growth Hormone ◽  
Protein Level ◽  
Hormonal Regulation ◽  
Mrna Level ◽  
Immunohistochemical Analysis ◽  
Upstream Region ◽  
Mrna Levels ◽  
Liver Region ◽  
Cytochrome P 450 ◽  
Cyp 3A

Most cytochrome P-450 enzymes are expressed characteristically in a zonated pattern in the liver. The factors responsible for this heterogenous expression are largely unknown. Here we report how growth hormone and tri-iodothyronine regulate the steroid-hydroxylating cytochrome P-450 (CYP) 3A forms, which are constitutively expressed mainly in the perivenous (downstream) liver region. By comparing cell lysates obtained from the periportal and perivenous acinar regions we observed that the elevated CYP3A expression observed after hypophysectomy was due mainly to a dramatic increase in the normally silent periportal region. This effect was particularly strong in females. Treatment with growth hormone re-established the perivenous expression pattern, a finding corroborated by immunohistochemical analysis of liver sections. Analysis of periportal and perivenous mRNA by reverse-transcriptase PCR demonstrated that in males the changes in CYP3A2 mRNA paralleled the changes at the protein level. In females, CYP3A2 mRNA was detected only after hypophysectomy, and the zonal protein changes seemed to be governed by changes in CYP3A1 mRNA levels. Treatment of hypophysectomized animals with tri-iodothyronine also suppressed the expression of CYP3A, both in males and females. However, this occurred almost exclusively in the periportal region. This was observed both at the protein level, as determined by immunoblotting and immunohistochemically, and at the CYP3A1 and 3A2 mRNA level. These results indicate that growth hormone and thyroid hormone regulate the expression of CYP3A genes zone-specifically by suppressing their transcription in the periportal (upstream) region of the liver.

scholarly journals Effects of Cyclamen trochopteranthum on hepatic drug-metabolizing enzymes

2011 ◽  
Vol 63 (3) ◽  
pp. 545-555 ◽  
Author(s):  
Sevki Arslan ◽  
Ozden Ozgun ◽  
Gurbet Celik ◽  
Asli Semiz ◽  
Olcay Dusen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Mrna Level ◽  
Drug Metabolizing Enzymes ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Metabolizing Enzymes ◽  
Hepatic Drug ◽  
Tuber Extract ◽  
Different Doses

The modulatory effects of the Cyclamen trochopterantum tuber extract on hepatic drug-metabolizing enzymes, including aniline 4-hydroxylase (A4H; CYP2E1), ethoxyresorufin O-deethylase (EROD; CYP1A), methoxyresorufin O-demethylase (MROD; CYP1A), caffeine N-demethylase (C3ND; CYP1A2) aminopyrene N-demethylase (APND; CYP2C6), and erythromycin N-demethylase (ERND; CYP3A1), were examined in vivo in rats. The activities of all of these enzymes were induced by the cyclamen extract. In addition, Western-blot and RT-PCR results clearly showed that CYP2E1, CYP1A1/CYP1A2 and CYP2C6 protein and mRNA levels were substantially increased by four different doses of cyclamen. Although, the CYP3A1 protein level was increased significantly, the mRNA level was not changed. These results indicate that cyclamen tuber extract might have a potential not only to inhibit and/or induce the metabolism of certain co-administered drugs but also influence the development of toxicity and carcinogenesis due to the induction of the cytochrome P450-dependent drug-metabolizing enzymes.

scholarly journals Aryl hydrocarbon receptor-dependence of dioxin’s effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components

2012 ◽  
Vol 90 (10) ◽  
pp. 1354-1363 ◽  
Author(s):  
Chunja Lee ◽  
David S. Riddick
Keyword(s):  
Growth Hormone ◽  
Cytochrome P450 ◽  
Aryl Hydrocarbon Receptor ◽  
Target Genes ◽  
Janus Kinase ◽  
Specific Gene ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Aryl Hydrocarbon ◽  
Signaling Components

The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands, and mediates adaptive and toxic responses to the environmental pollutant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts the expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially nonmetabolized AHR agonist, and Ahr −/− mice as the preferred model to determine the AHR-dependence of biological responses, we now show that 2 mouse hepatic STAT5b target genes, Cyp2d9, and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes.

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