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 administration, suggesting that Mrp2 limits the intestinal uptake of vinorelbine. Using P-glycoprotein (P-gp), Cyp3a-, and P-gp/Cyp3a knockout mice, we found that the absence of P-gp or Cyp3a resulted in increased vinorelbine plasma exposure, both after oral and intravenous administration. Surprisingly, P-gp/Cyp3a knockout mice displayed markedly lower vinorelbine plasma concentrations than wild-type mice upon intravenous administration but higher concentrations upon oral administration. This could be explained by highly increased formation of 4'-O-deacetylvinorelbine, an active vinorelbine metabolite, especially in P-gp/Cyp3a knockout plasma. Using wild-type and Cyp3a knockout liver microsomes, we found that 4'-O-deacetylvinorelbine formation was 4-fold increased in Cyp3a knockout liver and was not mediated by Cyp3a or other cytochrome P450 enzymes. In vitro incubation of vinorelbine with plasma revealed that vinorelbine deacetylation in Cyp3a and especially in P-gp/Cyp3a knockout mice but not in P-gp-deficient mice was strongly up-regulated. Metabolite formation in microsomes and plasma could be completely inhibited with the nonspecific carboxylesterase (CES) inhibitor bis(4-nitrophenyl) phosphate and partly with the CES2-specific inhibitor loperamide, indicating that carboxylesterase Ces2a, which was appropriately up-regulated in Cyp3a and especially in P-gp/Cyp3a knockout liver was responsible for the 4'O-deacetylvinorelbine formation. Such compensatory up-regulation can complicate the interpretation of knockout mouse data. Nonetheless, P-gp, Mrp2, Cyp3a, and Ces2a clearly restricted vinorelbine availability in mice. Variation in activity of their human homologs may also affect vinorelbine pharmacokinetics in patients.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Lagas JS,Damen CW,van Waterschoot RA,Iusuf D,Beijnen JH,Schinkel AHdoi
10.1124/mol.111.077099subject
Has Abstractpub_date
2012-10-01 00:00:00pages
636-44issue
4eissn
0026-895Xissn
1521-0111pii
mol.111.077099journal_volume
82pub_type
杂志文章abstract::Quinones undergo redox cycling and/or arylation reactions with key biomolecules involved with cellular Ca2+ regulation. The present study utilizes nanomolar quantities of the fluorogenic maleimide 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) to measure the reactivity of hyperreactive sulfhydryl moieti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1999-05-01 00:00:00
abstract::Although the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well established agents for the treatment of leukemia, controversies remain regarding their main mode of action. Previous evidence has suggested that although 6-TG exerts a cytotoxic effect through incorporation of 6-thioguanine nucleot...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.62.1.102
更新日期:2002-07-01 00:00:00
abstract::A novel cloned polymorphism of the human concentrative nucleoside transporter hCNT3 was described and functionally characterized. This variant consists of a T/C transition leading to the substitution of cysteine 602 by an arginine residue in the core of transmembrane domain 13. The resulting hCNT3(C602R) protein has t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.041848
更新日期:2008-02-01 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::Airway smooth muscle (ASM) cells can act as effector cells in the initiation and/or perpetuation of airway inflammation in asthma by producing various inflammatory chemokines or cytokines. Previous studies from our laboratory and others showed that the combination of tumor necrosis factor-alpha (TNFalpha) and interfer...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.030171
更新日期:2007-02-01 00:00:00
abstract::The mammalian copper transporter 1 (CTR1) is responsible for the uptake of copper from the extracellular space. In this study, we used an isogenic pair of CTR1(+/+) and CTR1(-/-) mouse embryo fibroblasts to examine the contribution of CTR1 to the influx of cisplatin (DDP), carboplatin (CBDCA), oxaliplatin (L-OHP), and...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.052381
更新日期:2009-02-01 00:00:00
abstract::Heart cells in culture need no external stimulation to contract; they beat rhythmically at a rate and intensity dependent on culture conditions. These cells respond to the general anesthetic 2-bromo-2-chloro-1,1,1-trifluorethane (halothane), with a loss of beating intensity and a lessening of beating rate. Increased c...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1983-03-01 00:00:00
abstract::G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in terminating signals initiated by agonist-bound GPCRs. However, chronic stimulation of GPCRs, such as that which occurs during heart failure, leads to the overexpression of GRKs and maladaptive downregulation of GPCRs on the cell surface. We previously...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.118661
更新日期:2020-06-01 00:00:00
abstract::We studied the mechanism by which the peptide omega-grammotoxin-SIA inhibits voltage-dependent calcium channels. Grammotoxin at concentrations of > 50 nM completely inhibited inward current carried by 2 mM barium through P-type channels in rat cerebellar Purkinje neurons when current was elicited by depolarizations up...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.6.1095
更新日期:1997-12-01 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::The D2 dopamine receptor (D2R) was examined for its ability to mediate nuclear factor-kappaB (NF-kappaB) activation through G proteins. Stimulation of D2R-transfected HeLa cells with its agonist quinpirole induced the expression of a NF-kappaB luciferase reporter and formation of NF-kappaB-DNA complex. This response w...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.2.447
更新日期:2003-08-01 00:00:00
abstract::Bufuralol 1'-hydroxylation is a prototypical reaction catalyzed by cytochrome P450 (P450) 2D6, an enzyme known to show debrisoquine/sparteine-type genetic polymorphism in humans. In the present study we further examined the roles of several human P450 enzymes, as well as P450 2D6, in the hydroxylation of (+/-)-bufural...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-09-01 00:00:00
abstract::The human caudate and putamen contain two high affinity binding sites for [3H]spiroperidol. Both of these affinity states exhibit dopaminergic selectivity. Ascorbic acid, at 0.1 mM, induces a slow loss of the low affinity component of [3H]spiroperidol binding in these tissues. The addition of guanyl nucleotides to the...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-02-01 00:00:00
abstract::Neuroactive steroids are efficacious potentiators of GABA-A receptors. Recent work has identified a site in the alpha1 subunit of the GABA-A receptor, that is essential for potentiation by steroids. However, each receptor contains two copies of the alpha1 subunit. We generated concatemers of subunits so that the alpha...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.053629
更新日期:2009-04-01 00:00:00
abstract::Olanzapine was shown to be oxidized to a reactive intermediate by HOCl, which is the major oxidant produced by activated neutrophils. A mass spectrum obtained using a flow system in which the reactants were fed into a mixing chamber and the products flowed directly into a mass spectrometer revealed a reactive intermed...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1998-06-01 00:00:00
abstract::Our previous studies suggested that the dNTP/dNDP transporter systems that exist in mitochondria for transporting dNTP/dNDP from the cytoplasm to the mitochondria for mitochondrial DNA (mtDNA) synthesis play a critical role in delayed cytotoxicity of anti-human immunodeficiency virus (HIV) dideoxynucleoside analogs in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.007120
更新日期:2005-02-01 00:00:00
abstract::Acetylsalicylic acid (aspirin) is a cyclooxygenase (COX) inhibitor, yet some of its therapeutic effects are thought to derive from mechanisms unrelated to prostaglandin synthesis inhibition. In human intestinal myofibroblasts, aspirin, at therapeutic doses, had the unexpected effect of inducing prolonged COX-2 express...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.2.470
更新日期:2004-02-01 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::The pharmacological effects of angiotensin II (AII) are potently inhibited by several peptide and recently synthesized nonpeptide AII receptor antagonists. The interaction of sarcosine1, isoleucine8-AII (sarile), sarcosine1,O-methyltyrosine4-AII (sarmesin), and the nonpeptide AII antagonists 2-n-butyl-4-chloro-5- hydr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-06-01 00:00:00
abstract::A1 adenosine receptors in bovine cerebral cortex have been solubilized and subjected to sedimentation analysis using sucrose density gradient centrifugation. Because the receptors bound both agonists and antagonists with high affinity after solubilization, receptors labeled with an agonist or an antagonist radioligand...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-09-01 00:00:00
abstract::Two human ovarian cancer cell lines were established from a patient before (PEO1) and after (PEO4) the onset of resistance to 5-fluorouracil (5-FU)/cisplatin-based chemotherapy. Using growth inhibition assays, we determined that the PEO4 line was almost 5-fold more resistant to 5-FU than the PEO1 line. The addition of...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-09-01 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::We determined the effect of flufenamic acid (FFA) and related derivatives on gap junction channel currents, applying the dual whole-cell patch-clamp technique to pairs of N2A neuroblastoma cells transfected with various connexins. FFA reduced gap junction channel currents in a reversible and concentration-dependent ma...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.6.1389
更新日期:2003-06-01 00:00:00
abstract::Corticotropin-releasing factor (CRF) receptors encoded by two distinct genes have recently been identified and termed CRF1 and CRF2. CRF and the non-mammalian-related peptide sauvagine bind to and activate CRF1 receptors with high affinity and equal potency. Although CRF is significantly weaker at the CRF2 receptor, s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::Nuclear receptors play important roles in the maintenance of the endocrine system, regulation of organ differentiation, and fetal development. Endocrine disruptors exert their adverse effects by disrupting the endocrine system via various mechanisms. To assess the effects of endocrine disruptors on nuclear receptors, ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.008409
更新日期:2005-03-01 00:00:00
abstract::The molecular determinants of high-affinity human ether-a-go-go-related gene (HERG) potassium channel blockade by methanesulfonanilides include two aromatic residues (Phe656 and Tyr652) on the inner helices (S6) and residues on the pore helices that face into the inner cavity, but determinants for lower-affinity HERG ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.001743
更新日期:2004-11-01 00:00:00
abstract::SR33557 belongs to a new class of molecules (indolizinsulfones) that act on the same receptor complex that has been characterized for other classical calcium channel effectors. The main binding properties of SR33557 to rabbit skeletal muscle are as follows. (i) Unlabeled SR33557 completely inhibits the specific bindin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-06-01 00:00:00
abstract::Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.097758
更新日期:2015-08-01 00:00:00
abstract::Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC pro...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.114.097477
更新日期:2015-06-01 00:00:00
abstract::Benzbromarone (BBR), a potent uricosuric agent for the management of gout, is known to cause fatal fulminant hepatitis. While the mechanism of BBR-induced idiosyncratic hepatotoxicity remains unelucidated, cytochrome P450 enzyme (CYP450)-mediated bioactivation of BBR to electrophilic reactive metabolites is commonly r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/molpharm.120.000086
更新日期:2021-01-12 00:00:00