Abstract:
:Dehydroepiandrosterone (DHEA) is a peroxisome proliferating agent when administered in pharmacological dosages, but it has not been shown to function through the peroxisome proliferator-activated receptor in cell-based assays. Because members of the thyroid hormone/vitamins A and D nuclear receptor subfamily, including PPAR, are known to modulate each other's function in gene expression by heterodimerization, we sought to establish whether DHEA and thyroid hormone interact to regulate several of the hepatic and renal enzymes associated with peroxisome proliferation, i.e., peroxisomal beta-oxidation and microsomal NADPH:cytochrome P450 oxidoreductase and the cytochromes P450 4A. In rats administered exogenous T3 to attain a hyperthyroid state, induction of the three isozymes of CYP4A (4A1, 4A2, and 4A3) by DHEA was suppressed > 60-80% at the mRNA level, with induction of CYP4A2 mRNA being completely inhibited. Nuclear run-on transcription assays indicated that this inhibitory effect was regulated at the level of transcription. Induction of hepatic peroxisomal beta-oxidation by DHEA or the peroxisome proliferator nafenopin was in large part unaffected by treatment of animals with T3 under any condition tested. Microsomal NADPH:cytochrome P450 oxidoreductase activity was induced by either DHEA or T3; cotreatment resulted in an additive induction. When animals were treated with a lower dose of exogenous T3 that rendered the animals slightly hyperthyroid, only induction of hepatic CYP4A2 mRNA by DHEA or nafenopin was significantly inhibited (> 80%) compared with euthyroid control animals. Animals that had been rendered hypothyroid through removal of the thyroid gland showed normal induction of CYP4A genes by DHEA in liver, suggesting that their induction by DHEA was not dependent on the presence of thyroid hormone. The administration of exogenous T3 to thyroidectomized rats in the presence of DHEA potently suppressed hepatic induction of all three genes at the mRNA and protein level. In experiments with cultured rat hepatocytes, physiological concentrations of T3 potently inhibited the induction of CYP4A2 mRNA levels by nafenopin but had little effect on induction of CYP4A1 or 4A3 mRNA. At higher T3 concentrations, the induction of CYP4A1/4A3 mRNA and protein was also inhibited. These results suggest that T3 modulates the expression of CYP4A2 at the level of transcription in physiologically relevant concentrations but that hyperthyroid conditions are required to suppress expression of CYP4A1/4A3 genes. In euthyroid rodent kidney, which only expresses CYP4A2 under either basal or DHEA-induced conditions, near-physiological levels of T3 caused potent suppression of peroxisome proliferator-dependent induction of CYP4A2 mRNA levels by either DHEA or nafenopin. In thyroidectomized rats, basal expression of CYP4A2 mRNA was decreased relative to euthyroid controls, but DHEA was as effective an inducer of this mRNA as it is in euthyroid rats. As seen in euthyroid rats, T3 administration potently suppressed DHEA induction of CYP4A2 mRNA levels under either basal or induced conditions. Although CYP4A expression was not derepressed in liver or kidneys of hypothyroid animals, our results indicated that the thyroid status of the animal did affect basal expression of CYP4A2, suggesting involvement of thyroid hormone or some other factor regulated by the thyroid gland on its constitutive expression.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Webb SJ,Xiao GH,Geoghegan TE,Prough RAsubject
Has Abstractpub_date
1996-02-01 00:00:00pages
276-87issue
2eissn
0026-895Xissn
1521-0111journal_volume
49pub_type
杂志文章abstract::Voltage-gated sodium channels are inhibited by many local anesthetics, antiarrhythmics, and antiepileptic drugs. The local anesthetic lidocaine appears to be able to access its binding site in the sodium channel only from the membrane phase or from the internal face of the channel. In contrast, the antiepileptic drug ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.090472
更新日期:2014-02-01 00:00:00
abstract::As a member of the transient receptor potential (TRP) ion channel superfamily, the ligand-gated ion channel TRPA1 has been implicated in nociceptive function and pain states. The endogenous ligands that activate TRPA1 remain unknown. However, various agonists have been identified, including environmental irritants (e....
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.033621
更新日期:2007-05-01 00:00:00
abstract::In this work, we evaluate the structural differences of transmembrane helix 3 in rhodopsin and the 5-hydroxytryptamine 1A (5-HT1A) receptor caused by their different amino acid sequence. Molecular dynamics simulations of helix 3 in the 5-HT1A receptor tends to bend toward helix 5, in sharp contrast to helix 3 in rhodo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.1.15
更新日期:2002-07-01 00:00:00
abstract::The level of cellular ceramide, an apoptotic rheostat, is increased by sphingomyelinase or de novo synthesis. The expression of the glutathione S-transferase (GST) gene, whose induction accounts for cell viability, is regulated by activation of CCAAT/enhancer binding protein-beta (C/EBPbeta) and NF-E2-related factor-2...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.6.1475
更新日期:2004-06-01 00:00:00
abstract::Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the researc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080689
更新日期:2013-01-01 00:00:00
abstract::The powerful analgesic effects of opioid drugs have captivated the interest of physicians and scientists for millennia, and the ability of opioid drugs to produce serious undesired effects has been recognized for a similar period of time (Kieffer and Evans, 2009). Many of these develop progressively with prolonged or ...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.119.119321
更新日期:2020-10-01 00:00:00
abstract::Aldose reductase (AKR1B1) is a critical drug target because of its involvement in diabetic complications, inflammation, and tumorigenesis. However, to date, development of clinically useful inhibitors has been largely unsuccessful. Cyclopentenone prostaglandins (cyPGs) are reactive lipid mediators that bind covalently...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.100693
更新日期:2016-01-01 00:00:00
abstract::The present study was conducted to establish a pharmacological method of controlling growth of vascular smooth muscle cells (VSMC) by blocking calcium entry. In cultured rat VSMC, 1 nM platelet-derived growth factor (PDGF) induced a biphasic elevation of cytoplasmic free calcium concentration, ([Ca2+]c). The second su...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-10-01 00:00:00
abstract::Variant neuroblastoma cell clones were selected for resistance to the cytotoxic effects of neurotoxins that cause persistent activation of sodium channels. Three classes of variant clones were obtained: sodium channel-deficient clones, which have markedly reduced numbers of functional sodium channels; scorpion toxin-r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-07-01 00:00:00
abstract::Autophagy is a response of cancer cells to various anticancer therapies. It is designated as programmed cell death type II and characterized by the formation of autophagic vacuoles in the cytoplasm. The Akt/mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase (p70S6K) and the extracellular signal-regul...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.033167
更新日期:2007-07-01 00:00:00
abstract::We have previously reported that endocytic sorting of ET(A) endothelin receptors to the recycling pathway is dependent on a signal residing in the cytoplasmic carboxyl-terminal region. The aim of the present work was to characterize the carboxyl-terminal recycling motif of the ET(A) receptor. Assay of truncation mutan...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.007013
更新日期:2005-05-01 00:00:00
abstract::CYP3A4 is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modificatio...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.117.108225
更新日期:2017-08-01 00:00:00
abstract::Lead (Pb(2+)) is a well-known inhibitor of voltage-dependent Ca(2+) channels in their native environments in several types of cells. However, its effects on discrete Ca(2+) channel phenotypes in isolation have not been well studied. We compared how specific subtypes of human neuronal high-voltage-activated Ca(2+) chan...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.6.1418
更新日期:2002-12-01 00:00:00
abstract::Neuronal cell lines provide a source of pure populations of neurons and allow the properties of many neurotransmitter receptors to be studied. However, none of these cells have been reported to express functional gamma-aminobutyric acid (GABA)A receptors. Indeed, there have been no reports of cell lines expressing fun...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-08-01 00:00:00
abstract::The levels of hepatic mRNAs for several enzymes involved in drug metabolism were measured following administration to rats of either phenobarbitone or 2-allyl-2-isopropylacetamide. There was a substantial elevation in the mRNA levels for cytochromes P450 IIB1, IIB2, and IIIA1, epoxide hydrolase, glutathione-S-transfer...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-10-01 00:00:00
abstract::Using [3H]leukotriene C4 (LTC4) and radioligand-binding techniques, specific leukotriene C4 binding sites have been identified in membranes derived from guinea pig ventricular myocardium. High performance liquid chromatography analyses indicated that, in the presence of the gamma-glutamyl transpeptidase inhibitor L-se...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-02-01 00:00:00
abstract::Studies in vertebrate neuromuscular synapses have revealed previously that ATP, via P2Y receptors, plays a critical role in regulating postsynaptic gene expressions. An equivalent regulatory role of ATP and its P2Y receptors would not necessarily be expected for the very different situation of the brain synapses, but ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.066506
更新日期:2010-12-01 00:00:00
abstract::n-Dodecylguanidine (C12-G) is an amphipathic compound with a guanidine moiety, which is positively charged at physiological pH, and a hydrophobic side chain. Its effects on an A-type K+ channel clone (rKv1.4) expressed in Xenopus oocytes were examined. C12-G caused a concentration-dependent (1-20 microM) positive shif...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-07-01 00:00:00
abstract::Cytosolic sulfotransferase 1C3 (SULT1C3) is the least characterized of the three human SULT1C subfamily members. Originally identified as an orphan SULT by computational analysis of the human genome, we recently reported that SULT1C3 is expressed in human intestine and LS180 colorectal adenocarcinoma cells and is upre...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.106005
更新日期:2016-11-01 00:00:00
abstract::The peroxisome proliferator-activated receptors (PPARs) represent pharmacological target molecules to improve insulin resistance in type 2 diabetes mellitus. Here we assessed a functional connection between pharmacological activation of PPAR and vascular endothelial growth factor (VEGF) expression in keratinocytes and...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.049395
更新日期:2008-10-01 00:00:00
abstract::Bovine pulmonary artery endothelial (CPAE) cells respond to bradykinin, and it has been suggested that the receptors on these cells do not fall into the normal B1/B2 classification of bradykinin receptors [J. Pharmacol. Exp. Ther. 244:646-649 (1988)]. The present study describes a detailed characterization of the subt...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-03-01 00:00:00
abstract::Comparative molecular field analysis (CoMFA) predicts that the large electrostatic field around the phosphate groups of ATP plays a crucial role in stabilizing the open state of the cardiac ryanodine receptor (RyR) channel. We therefore investigated the effects of adenosine-5'-(beta,gamma-methylenetriphosphate) (AMP-P...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.1.174
更新日期:2003-01-01 00:00:00
abstract::Rat cerebellar granule cells express 5-hydroxytryptamine (5-HT)2 receptors that mediate phosphoinositide turnover by a pertussis toxin-sensitive mechanism. Prestimulation of these neurons with 10 microM 5-HT or (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane [(+/-)-DOI], a putative 5-HT2 receptor agonist, resulted in ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-03-01 00:00:00
abstract::The binding of [3H]Hspiroperidol to D2 dopaminergic receptors in rat striatum was compared to the binding of [3H]dopamine to its binding sites. Both radioligands labeled apparently homogeneous populations of high affinity, stereoselective, saturable sites, determined from analysis of saturation isotherms. [3H]Spiroper...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-11-01 00:00:00
abstract::The cytotoxic efficacy of antitumor drugs targeted at DNA topoisomerase II (topo II) in many cases varies in direct proportion to cellular topo II content. To investigate the transcriptional control of the predominant alpha form of topo II, the 5' flanking region of the human topo II alpha gene (positions -562 to +90)...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-04-01 00:00:00
abstract::The chemical reaction of 1,4-benzoquinone with glutathione results in the formation of adducts that exhibit increasing degrees of glutathione substitution. Purification of these adducts and analysis by 1H and 13C nuclear magnetic resonance spectroscopy revealed the products of the reaction to be 2-(glutathion-S-yl)hyd...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-12-01 00:00:00
abstract::The small GTPase Rac1 has been widely implicated in mammary tumorigenesis and metastasis. Previous studies established that stimulation of ErbB receptors in breast cancer cells activates Rac1 and enhances motility via the Rac-guanine nucleotide exchange factor P-Rex1. As the Janus tyrosine kinase 2 (Jak2)/signal trans...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.084293
更新日期:2013-05-01 00:00:00
abstract::A nonnaturally occurring L-configuration nucleoside analog, L-beta-5-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil (L-BVOddU) selectively inhibited varicella-zoster virus growth in human embryonic lung (HEL) 299 cell culture with an EC(50) of 0.055 microM, whereas no inhibition of CEM and HEL 299 cell growth or ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.5.1109
更新日期:2000-11-01 00:00:00
abstract::The effects of the dihydropyridine calcium channel agonist Bay K 8644 on indo-1-loaded Jurkat human leukemia T lymphocytes was assessed by flow cytometry. Bay K 8644 from 10(-9) to 10(-4) M caused a dose-dependent rise in the intracellular free Ca concentration, an effect that was not mimicked by the dihydropyridine C...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-09-01 00:00:00
abstract::Type II DNA topoisomerases are targets of acridine drugs. Nine mutations conferring resistance to acridines were obtained by forced molecular evolution, using methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide (mAMSA), methyl N-(4'-(9-acridinylamino)-2-methoxy-phenyl) carbamate hydrochloride (mAMCA)...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.032953
更新日期:2007-04-01 00:00:00