Abstract:
:The anti-arrhythmic quinidine has been reported to be a competitive inhibitor of the catalytic activities of human liver P-450DB, including sparteine delta 2-oxidation and bufuralol 1'-hydroxylation, and we confirmed the observation that submicromolar concentrations are strongly inhibitory. Human liver microsomes oxidize quinidine to the 3-hydroxy (Km 4 microM) and N-oxide (Km 33 microM) products, consonant with in vivo observations. Both bufuralol and sparteine inhibited microsomal quinidine 3-hydroxylation. Liver microsomes prepared from DA strain rats showed a relative deficiency in quinidine 3-hydroxylase activity in females compared to males. These observations might suggest that quinidine oxidation is catalyzed by the same P-450 forms that oxidize debrisoquine, bufuralol, and sparteine; i.e., rat P-450UT-H and P-450DB. However, neither of these two purified enzymes catalyzed quinidine 3-hydroxylation, and anti-P-450UT-H, which strongly inhibits human liver microsomal bufuralol 1'-hydroxylation, did not substantially inhibit quinidine 3-hydroxylation or N-oxygenation. P-450MP, the human S-mephenytoin 4-hydroxylase, also does not appear to oxidize quinidine but P-450NF, the human nifedipine oxidase, does. Anti-P-450NF inhibited greater than 95% of the 3-hydroxylation and greater than 85% of the N-oxygenation of quinidine in several microsomal samples. Quinidine inhibited microsomal nifedipine oxidation and, in a series of human liver samples, rates of nifedipine oxidation were correlated with rates of quinidine oxidation. Thus, quinidine oxidation appears to be catalyzed primarily by P-450NF and not by P-450DB. Quinidine binds 2 orders of magnitude more tightly to P-450DB, which does not oxidize it, than to P-450NF, the major enzyme involved in its oxidation. The substrate specificity of human P-450NF is discussed further in terms of its regioselective oxidations of complex molecules including quinidine, aldrin, benzphetamine, cortisol, testosterone and androstenedione, estradiol, and several 2,6-dimethyl-1,4-dihydropyridines.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Guengerich FP,Müller-Enoch D,Blair IAsubject
Has Abstractpub_date
1986-09-01 00:00:00pages
287-95issue
3eissn
0026-895Xissn
1521-0111journal_volume
30pub_type
杂志文章abstract::Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. CYP2E1 has also been implicated in alcohol liver disease because of its contribution to oxidative stress. Previously, polymorphic alleles with mutations in i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::We showed previously that subtypes of alpha 1-adrenergic receptors can be differentiated by selective inactivation with chlorethylclonidine (CEC) [Mol. Pharmacol. 32:505-510 (1987)] or by their affinities for the competitive antagonist WB 4101 [Nature (Lond.) 329:333-335 (1987)]. Examining eight rat tissues, the propo...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-05-01 00:00:00
abstract::Tienilic acid-induced hepatitis is characterized by the presence of anti-liver and -kidney microsomal (anti-LKM2) autoantibodies in patient sera. Cytochrome P4502C9(CYP2C9), involved in the metabolism of tienilic acid, was shown to be a target for tienilic acid-reactive metabolites and for autoantibodies. To further i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-08-01 00:00:00
abstract::Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many p...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.2.269
更新日期:2002-02-01 00:00:00
abstract::The carbocyclic analogue of 5-nitro-2'-deoxyuridine (NO2dUrd), in which the sugar moiety is replaced by a cyclopentane ring and which was designated C-NO2dUrd, has been evaluated for its cytostatic, antimetabolic, and antitumor properties. The following findings are noted. C-NO2dUrd is about 500- to 2000-fold less inh...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-05-01 00:00:00
abstract::Post-transcriptional protein synthesis by GH3 cloned pituitary cells, which secrete prolactin and growth hormone, is dependent on Ca2+. The effects of antagonists of prolactin secretion were examined on overall protein synthesis in GH3 cells as a function of cellular Ca2+ depletion and restoration at varying concentra...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-04-01 00:00:00
abstract::The mouse 5-hydroxytryptamine4a (5-HT4a) receptor is an unusual member of the G protein-coupled receptor superfamily because it possesses two separate carboxyl-terminal palmitoylation sites, which may allow the receptor to adopt different conformations in an agonist-dependent manner (J Biol Chem 277:2534-2546, 2002). ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008748
更新日期:2005-05-01 00:00:00
abstract::Electrical recordings were made in Xenopus oocytes to study the modulatory effects of steroids on gamma-aminobutyric acid (GABA) receptors expressed by RNA from mammalian brain and retina. GABA responses expressed by rat cerebral cortex poly(A)+ RNA were bicuculline-sensitive Cl- currents mediated by GABAA receptors. ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-01-01 00:00:00
abstract::Bryostatin 1 and phorbol-12-myristate-13-acetate (PMA) are both potent activators of protein kinase C (PKC), although in primary mouse keratinocytes bryostatin 1 does not induce differentiation and blocks PMA-induced differentiation. We report here that in primary mouse keratinocytes PMA caused translocation of PKC-ep...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-11-01 00:00:00
abstract::Molecular cloning of the alpha 2A-adrenergic receptor has shown that this receptor is a member of the gene superfamily of guanine nucleotide-binding protein (G protein)-coupled receptors. The alpha 2A-adrenergic receptor expressed in Chinese hamster ovary (CHO) cells attenuates and potentiates forskolin-stimulated cAM...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-08-01 00:00:00
abstract::Epoxyeicosatrienoic acids (EETs), products of the cytochrome P-450 monooxygenase metabolism of arachidonic acid, can regulate the activity of ion channels. We examined the effects of EETs on cardiac L-type Ca2+ channels that play important roles in regulating cardiac contractility, controlling heart rate, and mediatin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.55.2.288
更新日期:1999-02-01 00:00:00
abstract::The deletion of Phe-508 (DeltaPhe508) constitutes the most prevalent of a number of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that cause cystic fibrosis (CF). This mutation leads to CFTR misfolding and retention in the endoplasmic reticulum, as well as impaired channel activity. The b...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.055608
更新日期:2009-06-01 00:00:00
abstract::The human dopamine and norepinephrine transporters (hDAT and hNET, respectively) control neurotransmitter levels within the synaptic cleft and are the site of action for amphetamine (AMPH) and cocaine. We investigated the role of a threonine residue within the highly conserved and putative phosphorylation sequence RET...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.069039
更新日期:2011-03-01 00:00:00
abstract::The interactions between beta-adrenergic receptor (beta AR) antagonists and the beta(2)AR were studied with the use of photoaffinity labels. A proteolytic map of the receptor was made and confirmed through amino-terminal amino acid sequencing by locating sites of derivatization. [125I]Iodoazidothiophenylalprenolol (IA...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-06-01 00:00:00
abstract::K201 (JTV-519) may prevent abnormal Ca(2+) leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca(2+)-stimulated ATPase (SERCA) and RyRs by K201. In isolated cardiac a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.102277
更新日期:2016-08-01 00:00:00
abstract::The peripheral cannabinoid receptor (CB2) is a G protein-coupled receptor that is both positively and negatively coupled to the mitogen-activated protein kinase (MAPK) and cAMP pathways, respectively, through a Bordetella pertussis toxin-sensitive G protein. CB2 receptor-transfected Chinese hamster ovary cells exhibit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-03-01 00:00:00
abstract::Taxanes act by inhibiting microtubule dynamics; in this study, we have investigated mitochondria as an additional target of taxanes. We incubated isolated mitochondria in the presence of taxanes with or without stimulation of the mitochondrial respiratory state. Results showed that they rapidly induced the loss of del...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.1.51
更新日期:2003-07-01 00:00:00
abstract::The highly conserved Arg in the so-called DRY motif (Asp-Arg-Tyr) at the intracellular end of transmembrane helix 3 is in general considered as an essential residue for G protein coupling in rhodopsin-like seven transmembrane (7TM) receptors. In the open reading frame 74 (ORF74) receptor encoded by equine herpesvirus ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.011239
更新日期:2005-07-01 00:00:00
abstract::Bordetella pertussis, the pathogen responsible for whooping cough, releases a soluble calmodulin-sensitive adenylate cyclase into its culture medium which enters several different types of animal cells and elevates intracellular cAMP. In this study, the influence of B. pertussis adenylate cyclase on intracellular cAMP...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-05-01 00:00:00
abstract::The metabotropic glutamate 5 receptor and the cannabinoid type 1 receptor are G protein-coupled receptors that are widely expressed in the central nervous system. Metabotropic glutamate 5 receptors, present at the postsynaptic site, are coupled to Gαq/11 proteins and display an excitatory response upon activation, whe...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.116.104372
更新日期:2016-11-01 00:00:00
abstract::Aflatrem, a mycotoxin from Aspergillus flavus, potentiates the gamma-aminobutyric acid (GABA)-induced chloride current. This positive allosteric regulatory action of aflatrem was quantitatively studied on the GABAA receptor channel expressed in Xenopus oocytes after injection with chick brain mRNA under voltage-clamp ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-03-01 00:00:00
abstract::Batrachotoxin (BTX), from South American frogs of the genus Phyllobates, irreversibly activates voltage-gated sodium channels. Previous work demonstrated that a phenylalanine residue approximately halfway through pore-lining transmembrane segment IVS6 is a critical determinant of channel sensitivity to BTX. In this st...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.4.905
更新日期:2002-04-01 00:00:00
abstract::Anandamide (AEA) and delta9-tetrahydrocannabinol (THC) are endogenous and exogenous ligands, respectively, for cannabinoid receptors. Whereas most of the pharmacological actions of cannabinoids are mediated by CB1 receptors, there is also evidence that these compounds can produce effects that are not mediated by the a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.019174
更新日期:2006-03-01 00:00:00
abstract::High-throughput screening has led to the identification of small-molecule blockers of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, but the structural basis of blocker binding remains to be defined. We developed molecular models of the CFTR channel on the basis of homology to the bac...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080267
更新日期:2012-12-01 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::The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.040741
更新日期:2008-03-01 00:00:00
abstract::Signaling by G-protein-coupled receptors is often considered a uniform process, whereby a homogeneously activated proportion of randomly distributed receptors are activated under equilibrium conditions and produce homogeneous, steady-state intracellular signals. While this may be the case in some biologic systems, the...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.115.100248
更新日期:2015-09-01 00:00:00
abstract::This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of ne...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.65.1.2
更新日期:2004-01-01 00:00:00
abstract::Cytochrome P450 2C6 (CYP2C6) is a developmentally regulated, constitutively expressed form of rat liver microsomal cytochrome P450 that in the liver of adult male rats is induced to a limited extent by phenobarbital. The gene is not expressed at detectable levels in the lung, kidney, or brain. It is expressed and indu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-07-01 00:00:00
abstract::Nitric oxide (NO) binds with high affinity to the heme of soluble guanylyl cyclase (sGC), resulting in accumulation of the second messenger cGMP in many biological systems. 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) was recently described as potent and selective inhibitor of sGC, providing an invaluable tool wi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-07-01 00:00:00