Abstract:
:Metabolism of [3H]-(+/-)-trans-1,2-dihydroxy-1,2-dihydrobenz[a] anthracene by liver microsomes isolated from control, phenobarbital-treated, and 3-methylcholanthrene-treated Long-Evans rats and from 3-methylcholanthrene-treated Sprague-Dawley rats was examined. Liver microsomes from both control and phenobarbital-treated rats metabolized the dihydrodiol at a rate of 0.5 nmol/nmole of cytochrome P450 per minute, whereas prior treatment of rats with 3-methylcholanthrene stimulated the rate of metabolism by 4-fold. Prior treatment of the rats caused marked differences in the regio- and stereoselectivity of the metabolism of this pseudo-diaxial dihydrodiol. In each case, the major metabolites were three bis-dihydrodiols and a pair of diastereomeric 1,2-diol-3,4-epoxides in which the benzylic 1-hydroxyl group is either cis or trans to the epoxide oxygen (diol epoxides-1 and -2, respectively). The presence of the diol epoxides in the incubation medium was inferred from the identification of their corresponding tetraols, which arise by hydrolysis of the diol epoxides on chromatography. Hepatic microsomes from control and phenobarbital-treated rats metabolized the 1,2-dihydrodiol predominantly to 1,2-diol-3,4-epoxides (68-85% of the total metabolites) whereas bis-dihydrodiols represented 28% and 13% of the total metabolites, respectively. In contrast, liver microsomes from 3-methylcholanthrene-treated rats of either strain metabolized the 1,2-dihydrodiol primarily to isomeric bis-dihydrodiols (51-56% of total metabolites), with diol epoxides accounting for only 36-38% of the total metabolites. Bis-dihydrodiol-1 (32-35% of the total metabolites) was formed in greater amounts (2- to 4-fold) than either bis-dihydrodiols-2 or -3, which were formed in about equal amounts and have identical absorption spectra. The ratio of the diastereomeric 1,2-diol-3,4-epoxides-1 and -2 was highly dependent upon the preparation used. For microsomes from control and phenobarbital-treated rats, this ratio was between 3:1 and 4:1 whereas microsomes from 3-methylcholanthrene-treated rats (greater than 70% cytochrome P-450c) gave a ratio of between 1:1.5 and 1:2. The basis for this ratio in the latter case was explained by examination of the products formed from the (+)-(1S,2S)-and (-)-(1R,2R)-enantiomers of the dihydrodiol on metabolism by a highly purified system reconstituted with cytochrome P-450c. The (-)-isomer is a 3-fold better substrate than the (+)-isomer and forms only the diol epoxide-2 diastereomer, whereas the (+)-isomer forms much more diol epoxide-1 than diol epoxide-2 diastereomer.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Vyas KP,van Bladeren PJ,Thakker DR,Yagi H,Sayer JM,Levin W,Jerina DMsubject
Has Abstractpub_date
1983-07-01 00:00:00pages
115-23issue
1eissn
0026-895Xissn
1521-0111journal_volume
24pub_type
杂志文章abstract::Platelet-activating factor (PAF) receptor-coupled activation of phosphoinositide-specific phospholipase C (PLC) was studied in platelets that were made refractory, by short-term pretreatments, to either PAF or thrombin. Generation of [3H]inositol triphosphate ( [3H]IP3) was monitored specifically for this purpose. [3H...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-01-01 00:00:00
abstract::The N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors are known to be inhibited by 3-amino-1-hydroxy-2-pyrrolidone (HA-966) and 7-chlorokynurenic acid (Cl-KYN), which act at the glycine-regulated allosteric modulatory center. In this work we show that, in synaptic membranes prepared from rat brain, Cl-KYN and ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-12-01 00:00:00
abstract::2-Hydroxy-4(-2,2,3,3,3-pentafluoropropoxy)-benzoic acid (UR-1505), a new molecule chemically related to salicylic acid, has immunomodulator properties and is currently under clinical development for treatment of atopic dermatitis. The present work describes the immunomodulatory profile of UR-1505. UR-1505 targets T ce...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.035212
更新日期:2007-08-01 00:00:00
abstract::Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepression. However, effective...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.006254
更新日期:2005-03-01 00:00:00
abstract::Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼ 15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the pro...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.115.102301
更新日期:2016-03-01 00:00:00
abstract::Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both n...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.2.170
更新日期:2001-02-01 00:00:00
abstract::The chemokine receptor CCR2 is a G protein-coupled receptor that is activated primarily by the endogenous CC chemokine ligand 2 (CCL2). Many different small-molecule antagonists have been developed to inhibit this receptor, as it is involved in a variety of diseases characterized by chronic inflammation. Unfortunately...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.086850
更新日期:2013-10-01 00:00:00
abstract::The effects of tournefolic acid B (TAB) and two ester derivatives, TAB methyl ester (TABM) and TAB ethyl ester (TABE), on N-methyl-D-aspartate (NMDA)-mediated excitotoxicity and the underlying mechanisms were investigated. Treatment with 50 microM NMDA elicited neuronal death by 48.7 +/- 5.1%, coinciding with the appe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.018770
更新日期:2006-03-01 00:00:00
abstract::Because cytotoxicity by an alkylating agent such as N-methyl-N'-nitrosoguanidine is markedly increased in adenine methylase-deficient dam-3 Escherichia coli, it was of interest to assess whether mismatch repair was similarly important in the repair of DNA damage induced by cis-diamminedichloroplatinum(II) (CDDP). The ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-07-01 00:00:00
abstract::Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CY...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::Some biochemical and pharmacological properties of a novel, potent inhibitor of cyclic AMP phosphodiesterase, N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one) butyramide (RS-82856), were investigated. RS-82856 selectively inhibits the high affinity form of cyclic AMP phosphodiesterase ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-06-01 00:00:00
abstract::The role of mobilization of intracellular Ca2+ in the adrenergic-stimulated cAMP accumulation in rat pinealocytes was investigated with thapsigargin, an agent that inhibits endoplasmic reticulum Ca2+-ATPase. It was found that although thapsigargin alone had no effect on the basal cAMP accumulation, it potentiated the ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-06-01 00:00:00
abstract::Retinoid X receptor α [RXRα; nuclear receptor (NR)2B1] is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathologic conditions. During inflammation, RXRα undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, wh...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.085555
更新日期:2013-08-01 00:00:00
abstract::The ability of four antidepressant drugs, imipramine, alaproclate, norzimelidine, and fluvoxamine, to inhibit serotonin transport into platelet plasma membrane vesicles was tested over a range of external Na+ concentrations. Imipramine affinity, as we previously reported [J. Biol. Chem. 258:6115-6119 (1983)] increases...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-06-01 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::Chronic stimulation of beta-adrenoceptors leads to increased mRNA and protein levels of pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G proteins) in the heart. In the present study the time course is reported of the effect of isoprenaline infusions on myocardial mRNA levels of Gi alpha-2, Gi alp...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-11-01 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::A human recombinant L-type Ca2+ channel (alpha1C,77) was coexpressed with the rat angiotensin AT1A receptor in Xenopus laevis oocytes. In oocytes expressing only alpha1C,77 channels, application of human angiotensin II (1-10 microM) did not affect the amplitude or kinetics of Ba2+ currents (IBa). In sharp contrast, in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.54.6.1106
更新日期:1998-12-01 00:00:00
abstract::Metyrapone administration to 21- and 90-day-old male rats causes a transcriptional induction of the hepatic glucocorticoid-inducible CYP3A1 gene within an hour as determined by nuclear run-on experiments. Analyses performed 24 hr after metyrapone administration in both ages of rat demonstrate that the transcriptional ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-10-01 00:00:00
abstract::Smooth muscle preparations of human aorta or pig coronary arteries contain nearly equal amounts of cGMP-dependent protein kinase isozymes (cGMP kinase I alpha and I beta). In order to understand the roles of these isozymes in relaxing vascular smooth muscle, several new cGMP analogs were synthesized and tested for pot...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-07-01 00:00:00
abstract::We synthesized a novel platinum drug, cis-[PtCl(NH3)2(N7-ACV)]+, in which ACV is the antiviral drug acyclovir [a deoxyriboguanosine analogue, 9-(2-hydroxyethoxymethyl)guanine]. This new compound exhibits antiviral efficacy in vitro and exhibits an antitumor activity profile different from that of cisplatin [Metal-Base...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-05-01 00:00:00
abstract::A recently isolated monoclonal antibody was found to be a potent and powerful inhibitor of the catalytic activity of rabbit brain acetylcholinesterase (AChE; acetylcholine acetylhydrolase, EC 3.1.1.7), with an IC50 of about 1 nM and a maximal inhibition of at least 90%. The antibody increased the optimal concentration...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-12-01 00:00:00
abstract::Valproic acid (VPA) is a widely used antiepileptic agent that is undergoing clinical evaluation for anticancer therapy. We assessed the effects of VPA on angiogenesis in vitro and in vivo. In human umbilical vein endothelial cells, therapeutically relevant concentrations of VPA (0.25 to 1 mM) inhibited proliferation, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.3.520
更新日期:2004-03-01 00:00:00
abstract::We investigated the interactions of the anticancer drug vinorelbine with drug efflux transporters and cytochrome P450 3A drug-metabolizing enzymes. Vinorelbine was transported by human multidrug-resistance associated protein (MRP) 2, and Mrp2 knockout mice displayed increased vinorelbine plasma exposure after oral adm...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.077099
更新日期:2012-10-01 00:00:00
abstract::Previously we demonstrated that aldehyde dehydrogenase (ALDH) 1a1 is the major ALDH expressed in mouse liver and is an effective catalyst in metabolism of lipid aldehydes. Quantitative real-time polymerase chain reaction analysis revealed a ≈2.5- to 3-fold induction of the hepatic ALDH1A1 mRNA in mice administered eit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.078147
更新日期:2012-10-01 00:00:00
abstract::Many Gi-coupled receptors are known to interact with the pertussis toxin (PTX)-insensitive Gz protein. Given that the alpha subunits of Gi and Gz share only 60% identity in their amino acid sequences, their receptor-interacting domains must be highly similar. By swapping the carboxyl termini of alpha i2 and alpha z wi...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.1.38
更新日期:1997-07-01 00:00:00
abstract::The effect of breast cancer resistance protein (Bcrp/Abcg2) on the disposition of the phytoestrogens daidzein, genistein, and coumestrol was investigated using Bcrp(-/-) mice. Expression of the genes for either mouse Bcrp or human BCRP in MDCK II cells induced apically directed transport of the three phytoestrogens, w...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.034751
更新日期:2007-10-01 00:00:00
abstract::In the present study we have investigated the capacity of various compounds sterically related to indolo[3,2-b]carbazole to inhibit specific 2,3,7,8-tetrachloro[1,6-3H]dibenzo-p-dioxin binding in rat liver cytosol, as analyzed by electrofocusing in polyacrylamide gels. When the two nitrogen atoms of indolo[3,2-b]carba...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-08-01 00:00:00
abstract::Multidrug and toxin extrusion 1 (MATE1/SLC47A1) is important for excretion of organic cations in the kidney and liver, where it is located on the luminal side. Although its functional and regulatory characteristics have been clarified, its pharmacokinetic roles in vivo have yet to be elucidated. In the present study, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.056242
更新日期:2009-06-01 00:00:00
abstract::In this study, the expression of CYP26 is examined in relation to retinoid-induced mucosecretory differentiation in human tracheobronchial epithelial (HTBE) cells and compared with that in human lung carcinoma cell lines. In HTBE cells, retinoic acid (RA) inhibits squamous differentiation and induces mucous cell diffe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.3.483
更新日期:2000-09-01 00:00:00