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-transferase Ya/Yc subunit, UDP-glucuronosyltransferase isoenzyme (UDPGTr-2), NADPH-cytochrome P450 oxidoreductase, and 5-aminolevulinate synthase. When rats were treated with hemin, together with inducing drug, there was a marked reduction in the induced levels of these mRNAs, with decreases in the range of 55-95%. Basal levels of these mRNAs in the noninduced rat liver were also lowered by hemin administration. Nuclear run-on transcriptional experiments showed that hemin administration substantially lowered both the basal and drug-induced transcriptional activities of the genes for cytochrome P450IIB1/IIB2 and 5-aminolevulinate synthase. In contrast, the mRNA for heme oxygenase was elevated by hemin treatment, whereas the mRNA levels of beta-actin, albumin, and ornithine transcarbamylase, used as controls, were not affected. Treatment of rats with clofibrate resulted in increased levels of mRNA for cytochrome IVA1 and, in addition, those for cytochromes P450IIB1 and P450IIB2. Hemin administration repressed the induction of mRNA levels for cytochromes P450IIB1 and IIB2 but not that for cytochrome P450 IVA1. Additionally, the induction of P450IAI by beta-naphthoflavone was not affected by hemin. The results suggest that heme may negatively control the induction of cytochromes P450IIB1 and IIB2 and other hepatic enzymes by phenobarbitone and phenobarbitone-like drugs and perhaps play a role in regulating drug metabolism. There is, however, no evidence at present as to whether heme has a direct role in such a mechanism or whether injected hemin promotes a secondary response.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Srivastava G,Hansen AJ,Bawden MJ,May BKsubject
Has Abstractpub_date
1990-10-01 00:00:00pages
486-93issue
4eissn
0026-895Xissn
1521-0111journal_volume
38pub_type
杂志文章abstract::Three different cDNA clones, namely DM1-1, Dah1, and Dah2, encoding hepatic cytochrome P-450, were isolated from a cDNA library in lambda gt11 constructed from liver RNA of polychlorinated biphenyl-treated beagle dogs. DM1-1 was 1857 base pairs (bp) long and encoded a polypeptide of 457 residues. Dah1 was 2394 bp long...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-11-01 00:00:00
abstract::TWIK-related K(+) 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. Fenamates such as FFA (flufenamic acid; 2-{[3...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.091199
更新日期:2014-05-01 00:00:00
abstract::Previous studies have demonstrated that cotreatment with mitogen activated-protein kinase kinase (MEK) 1/2 inhibitors (e.g., PD184352) and the checkpoint abrogator 7-hydroxystaurosporine (UCN-01) dramatically induces apoptosis in a variety of human leukemia and multiple myeloma cell types. The purpose of this study wa...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.6.1402
更新日期:2003-12-01 00:00:00
abstract::Receptors from distant species may have conserved functions despite significant differences in protein sequences. Whereas the noncritical residues are often changed in distant species, the amino acids critical in receptor functions are often conserved. Studying the conserved residues between receptors from distant spe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.074500
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abstract::Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.1.143
更新日期:2003-07-01 00:00:00
abstract::The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications, but, if excessively propagated downstream, would introduce biologic noise compromising cognate ligand detection. We asked whether cells have the ability to lim...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.106369
更新日期:2017-02-01 00:00:00
abstract::This study identifies signaling pathways activated by the beta(2)-/beta(3)-adrenoceptor (AR) agonist zinterol, the selective beta(3)-AR agonist L755507, and the selective beta(3)-AR antagonist L748337 in CHO-K1 cells expressing human beta(3)-adrenoceptors. Zinterol and L755507 caused a robust concentration-dependent i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.046979
更新日期:2008-11-01 00:00:00
abstract::We present a mechanism for agonist-promoted alpha(2A)-adrenergic receptor (alpha(2A)-AR) activation based on structural, pharmacological, and theoretical evidence of the interactions between phenethylamine ligands and alpha(2A)-AR. In this study, we have: 1) isolated enantiomerically pure phenethylamines that differ b...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.5.1343
更新日期:2001-05-01 00:00:00
abstract::Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechani...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.4.674
更新日期:2001-04-01 00:00:00
abstract::TNP-ATP has become widely recognized as a potent and selective P2X receptor antagonist, and is currently being used to discriminate between subtypes of P2X receptors in a variety of tissues. We have investigated the ability of TNP-ATP to inhibit alpha,beta-methylene ATP (alpha,beta-meATP)-evoked responses in 1321N1 hu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.6.1502
更新日期:2000-12-01 00:00:00
abstract::Metabolism of the pulmonary toxin, 4-ipomeanol, in microsomal preparations from rabbit liver and lung and in purified cytochrome P-450-dependent monooxygenase systems was investigated. The rate of formation of reactive electrophilic products from 4-ipomeanol was estimated by measuring covalent binding to protein or gl...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-11-01 00:00:00
abstract::The aim of this study was to use pharmacological inhibition of protein kinase A and mutation of potential protein kinase A phosphorylation sites to determine the role of protein kinase A-catalyzed phosphorylation of the dopamine D(1) receptor in agonist-stimulated desensitization and internalization of the receptor. T...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.4.806
更新日期:2002-04-01 00:00:00
abstract::We have observed that rodent cell lines (mouse, hamster) contain approximately 10 times the levels of dihydrofolate reductase as human cell lines, yet the sensitivity to methotrexate (ED(50)), the folate antagonist that targets this enzyme, is similar. Our previous studies showed that dihydrofolate reductase protein l...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.055772
更新日期:2009-10-01 00:00:00
abstract::Pancreatic cancer is one of the most lethal types of tumors with no effective therapy available; is currently the third leading cause of cancer in developed countries; and is predicted to become the second deadliest cancer in the United States by 2030. Due to the marginal benefits of current standard chemotherapy, the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.118.115444
更新日期:2019-07-01 00:00:00
abstract::mRNA levels for the protooncogene c-fos, measured by Northern blot analysis, were greatly increased in brains of mice undergoing ethanol withdrawal seizures. This increase was transient (levels were increased at the time of the seizure and returned to normal by 24 hr or less after seizure) and was larger in hippocampu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-03-01 00:00:00
abstract::Angiotensin II (AII) stimulates rapid increases in cytosolic Ca2+ concentrations in Xenopus laevis oocytes after binding to specific receptors located in the surrounding follicular cells. In follicular oocytes, the peptide AII receptor antagonists saralasin (IC50 = 25 nM) and CGP 42112A (IC50 = 400 nM) were orders of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-02-01 00:00:00
abstract::cRNAs encoding the kappa-opioid receptor and an inwardly rectifying, G protein-coupled, K+ channel were coinjected into Xenopus oocytes. The effects of kappa-opioid receptor agonists and antagonists on the membrane currents in these oocytes were studied using the two-electrode voltage-clamp technique. The kappa-opioid...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
abstract::[3H]Dihydroalprenolol ([3H]DHA) has been used extensively in receptor binding studies to measure beta-adrenergic receptors in the central nervous system. Usually, nonspecific binding has been defined by high concentrations of the beta-adrenergic receptor agonist isoproterenol or antagonists such as alprenolol or propr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-07-01 00:00:00
abstract::SC-54628 [1-(2-methylphenyl)-4-butyl-1,3-dihydro-3-[[6-[2-(1H- tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one] and its 1-(2,6-dimethylphenyl)-2H-imidazol-2-one derivative SC-54629 were potent inhibitors of 125I-angiotensin II (125I-AII) binding to rat adrenal cortex angiotensin type 1 (AT1) receptors. SC-...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract::We have studied the mechanism of action of Arg(*)-Arg-Nal(2)-Cys(1x)-Tyr-Gln-Lys-(d-Pro)-Pro-Tyr-Arg-Cit-Cys(1x)-Arg-Gly-(d-Pro)(*) (POL3026), a novel specific beta-hairpin mimetic CXC chemokine receptor (CXCR)4 antagonist. POL3026 specifically blocked the binding of anti-CXCR4 monoclonal antibody 12G5 and the intrace...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.042911
更新日期:2008-04-01 00:00:00
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journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.6.1309
更新日期:2003-12-01 00:00:00
abstract::The highly specialized metabotropic glutamate receptor type 6 (mGluR6) is postsynaptically localized and expressed only in the dendrites of ON bipolar cells. Upon activation of mGluR6 by glutamate released from photoreceptors, a nonselective cation channel is inhibited, causing these cells to hyperpolarize. Mutations ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.058628
更新日期:2009-11-01 00:00:00
abstract::Ethylketocyclazocine (EKC) binds to two sites on NCB-20 neuroblastoma X Chinese hamster brain hybrid cells (KDH = 2 nM, Bmax = 21,000 sites/cell; KDL = 27 nM, Bmax = 140,000 sites/cell. The high-affinity site has been characterized as a delta opiate receptor. The low-affinity site is relatively benzomorphan-specific; ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-03-01 00:00:00
abstract::The mitogen-activated protein kinase (MAPK) pathway plays a pivotal role in intracellular signaling, and this cascade may impinge on cAMP response elements (CREs) of target genes. Both the MAPK pathway and chromogranin A expression may be activated by cytosolic calcium influx, and calcium-dependent signals map onto th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.54.1.59
更新日期:1998-07-01 00:00:00
abstract::In previous studies, we have shown that mouse RAW 264.7 macrophages possess pyrimidinoceptors, coupled to a phosphoinositide-specific phospholipase C, with a higher specificity for UTP than for ATP. In the current study, we explored the mechanism involved in the UTP-induced intracellular acidification seen in this cel...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.2.313
更新日期:1998-02-01 00:00:00
abstract::[This corrects the article on p. 21 in vol. 81, PMID: 21984254.]. ...
journal_title:Molecular pharmacology
pub_type: 已发布勘误
doi:10.1124/mol.115.075234err
更新日期:2016-01-01 00:00:00
abstract::The ADP-sensitive and K+ -sensitive phosphorylated forms of Na,K-ATPase (E1P and E2P, respectively) are believed to be the main phosphorylated intermediates of Na,K-ATPase. In the presence of 100 mM Na+, E2P is the major component of the phosphorylated form in all native Na,K-ATPase preparations known, including the m...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-11-01 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::Lack of high potency agonists has restricted analysis of the G protein-coupled receptor GPR35. Moreover, marked variation in potency and/or affinity of current ligands between human and rodent orthologs of GPR35 has limited their productive use in rodent models of physiology. Based on the reported modest potency of th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.089482
更新日期:2014-01-01 00:00:00
abstract::Peroxisome proliferator-activated receptor δ (PPARδ) has been implicated in vascular pathophysiology. However, its functions in atherogenic changes of the vascular wall have not been fully elucidated. PPARδ activated by GW501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]ph...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.104679
更新日期:2016-11-01 00:00:00