Pál Szabó

Hungarian Academy of Sciences, Budapeŝto, Budapest, Hungary

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Publications (33)80.09 Total impact

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    ABSTRACT: Baicalein, the aglycone formed by hydrolysis of baicalin in the intestine, is well absorbed by passive diffusion but subjected to extensive intestinal glucuronidation. Efflux of baicalin, the low passive permeability glucuronide of baicalein from enterocytes, likely depends on a carrier-mediated transport. The present study was designed to explore potential drug-herb interaction by investigating the inhibitory effect of baicalin on the transport of reporter substrates by transporters and to identify the transporters responsible for the efflux of baicalin from enterocytes and hepatocytes. The interaction of baicalin with specific ABC transporters was studied using membranes from cells overexpressing human BCRP, MDR1, MRP2, MRP3 and MRP4. Baicalin was tested for its potential to inhibit vesicular transport by these transporters. The transport of baicalin by the selected transporters was also investigated. Transport by BCRP, MRP3 and MRP4 was inhibited by baicalin with an IC50 of 3.41 ± 1.83 μM, 14.01 ± 2.51 μM and 14.39 ± 5.69 μM respectively. Inhibition of MDR1 (IC50 = 94.84 ± 31.10 μM) and MRP2 (IC50 = 210.13 ± 110.49 μM) was less potent. MRP2 and BCRP are the apical transporters of baicalin that may mediate luminal efflux in enterocytes and biliary efflux in hepatocytes. The basolateral efflux of baicalin is likely mediated by MRP3 and MRP4 both in enterocytes and hepatocytes. Via inhibition of transport by ABC transporters, baicalin could interfere with the absorption and disposition of drugs. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Sep 2015 · Phytotherapy Research
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    ABSTRACT: The original aim of this study was to develop a method for the determination of baicalin from membrane vesicles. The unconventional chromatographic separation ("inverse gradient elution" on a reversed phase column) was due to a lucky chance, which is detailed and discussed in this study. The validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is proved to be sensitive, rapid and selective. Chromatographic separation was performed on a Zorbax SB-C8 column (250mm×4.6mm, i.d.; 5μm) with 0.1% formic acid in water and methanol by linear gradient elution. Quantification of baicalin was determined by multiple reaction monitoring (MRM) mode using electrospray ionization (ESI). The calibration curve was linear (r=0.9987) over the concentration range from 1 to 1000nM. The coefficient of variation and relative error of baicalin for intra- and inter-assay at three quality control (QC) levels were 2.0-10.2% and -6.1 to 6.7%, respectively. The lower limit of quantification (LLOQ) for baicalin was 1nM (0.446ng/ml), without preconcentration of the sample. This method was subsequently applied to vesicular transport assays of baicalin in membrane vesicles successfully. The developed method can open up new area of research in the chromatographic separation of flavonoids and their glucuronides. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Apr 2015 · Journal of Pharmaceutical and Biomedical Analysis
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    ABSTRACT: Sandwich culture of hepatocytes is commonly applied for the prediction of in vivo biliary clearance (CLbil). In this paper, we present a modified procedure for the determination of in vitro CLbil in sandwich culture of rat hepatocytes, which allows the estimation of the impact of uptake processes on the overall CLbil. The main point of this modification is the separation of uptake and efflux processes. Ten drugs from four biopharmaceutics drug disposition classification system classes were chosen in order to demonstrate the advantages of this method: 1) the uptake is performed identically before the canaliculi are opened, thus the efflux starts at the same intracellular concentration of the drugs and the effect of Ca2+/Mg2+ depletion on the uptake is excluded; 2) exact intracellular concentrations can be measured at the start and at the end of the efflux; 3) the biliary clearance can be determined irrespective of the uptake; 4) the canalicular and the sinusoidal transport can be measured simultaneously; 5) drug-drug interactions concerning uptake and efflux transporters can be estimated independently. Depending on the degree of uptake, CLbil,app (calculated using the concentration of drugs in the medium) was significantly higher (sulfasalazine, fluvastatin, rosuvastatin, atorvastatin) or lower (pravastatin, procainamide) than CLbil,int (calculated using the intracellular concentration of drugs). When the uptake had no impact on the CLbil, the apparent and intrinsic CLbil did not differ significantly (lovastatin, rifampicin, quetiapine). Our results confirm that transporters may play a significant role in the uptake of drugs both with high and poor permeability and solubility.
    No preview · Article · Jan 2015 · Drug Metabolism Letters
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    ABSTRACT: Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity.
    No preview · Article · Apr 2013 · Bioorganic & medicinal chemistry
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    ABSTRACT: Four novel (1–4) and one known (5) diterpene polyesters with the jatrophane skeleton were isolated from a methanol extract of the aerial parts of the East Asian weed Euphorbia mongolica Prokh. The isolated compounds were characterized structurally and evaluated for multidrug resistance (MDR) reversing activity on human MDR gene-transfected L5178 mouse lymphoma cells; all these compounds were found to modulate the intracellular drug accumulation. The results highlighted some aspects of the structural requirements of jatrophane diterpenes as MDR modulators.
    No preview · Article · Oct 2012 · Planta Medica
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    ABSTRACT: Glutamate and γ-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters. Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na+ concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg2+] in vitro model of epilepsy. Under in vivo conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions. The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamatergic excitation into GABAergic inhibition providing an adjustable, in situ negative feedback on the excitability of neurons.
    Full-text · Article · Mar 2012 · BMC Biology
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    ABSTRACT: Multiple chromatographic separations of the CHCl3-soluble extract of the roots of Echinacea purpurea led to the isolation of 19 compounds. Four natural products, three alkamides and nitidanin diisovalerianate, were identified, and five further compounds were detected for the first time in this species. Additionally, 10 known E. purpurea metabolites were isolated. The structures were determined by mass spectrometry and advanced 1D and 2D NMR techniques. The bioactivity of the isolated compounds was studied in [35S]GTPγS-binding experiments performed on rat brain membrane preparations. Both partial and inverse agonist compounds for cannabinoid (CB1) receptors were identified among the metabolites, characterized by weak to moderate interactions with the G-protein signaling mechanisms. The G-protein-modulating activities of the Echinacea compounds are rather far from the full agonist effects seen with the CB1 receptor agonist reference compound arachidonyl-2′-chloroethylamide (ACEA). However, upon coadministration with ACEA, a number of them proved capable of inhibiting the stimulation of the pure agonist, thereby demonstrating cannabinoid receptor antagonist properties.Graphical abstractThree alkamides and nitidanin diisovalerianate were identified, together with 14 known alkamides and one sesquiterpene from the roots of Echinacea purpurea. Their interaction with G-protein-coupled cannabinoid receptors were examined..Highlights► Four natural products, three alkamides and one neolignan, were identified in the roots of Echinacea purpurea. ► Four further known alkamides and one sesquiterpene were detected for the first time in this species. ► Ten known E. purpurea alkamides were isolated. ► Their cannabinoid receptor activity in [35S]GTPγS-binding assay were investigated on rat brain membrane preparations. ► Both partial and inverse agonist compounds were identified.
    Full-text · Article · Oct 2011 · Phytochemistry
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    ABSTRACT: Phytochemical study of whole, undried plants of Euphorbia esula led to the isolation of six new (1-6) jatrophane diterpene polyesters, named esulatins H-M, together with the known compounds 2α,3β,5α,7β,15β-pentaacetoxy-9α-nicotinoyloxyjatropha-6(17),11-dien-14-one (7), salicinolide (8), and euphosalicin (9). The structures and relative configuration of 1-6 were established on the basis of extensive spectroscopic analysis, including HRESIMS and one- and two-dimensional NMR techniques. All these compounds, together with diterpenes (10-14) isolated previously from this plant, were evaluated for their antiproliferative activity against HeLa, Ishikawa, and MCF7 cells. The multidrug-resistance-reversing activities were also investigated on L5178 mouse lymphoma cells transfected with the pHa MDR1/A retrovirus DNA. Preliminary structure-activity relationship data are discussed.
    Full-text · Article · Jun 2011 · Journal of Natural Products
  • Katalin Daragics · Pál Szabó · Péter Fügedi
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    ABSTRACT: Reductive ring openings of 3-O-benzoyl-4,6-O-benzylidene-D-glucopyranosides with BH(3)·NMe(3)-AlCl(3) are accompanied by side reactions, such as debenzoylation and reduction of the benzoate to benzyl ether. This phenomenon was rationalized by aluminium chelate formation between the O-4 acetal and the benzoyl carbonyl group oxygens. It was also shown that these side reactions can be eliminated by using BH(3)·THF as the reducing agent.
    No preview · Article · May 2011 · Carbohydrate research
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    ABSTRACT: Phytochemical study of the aerial parts of Euphorbia grandicornis led to the isolation of two new tigliane diterpenes, 16-angeloyloxy-13α-isobutanoyloxy-4β,9α,20-trihydroxytiglia-1,5-diene-3,7-dione (1) and 16-angeloyloxy-13α-isobutanoyloxy-4β,9α,7β-trihydroxytiglia-1,5-dien-3-one (2). The structures and relative configuration of the new compounds were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments ((1)H NMR, JMOD, (1)H-(1)H COSY, NOESY, HSQC, and HMBC), mass spectrometry, and comparison with literature data. The biogenesis of 1 and 2 with respect to the unusual 5-en-7-one and 5-en-7-ol moieties is also discussed.
    Full-text · Article · Feb 2011 · Journal of Natural Products
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    ABSTRACT: Ivermectin is an antiparasitic drug frequently administered to humans. It has a limited brain exposure that is attributed to the efflux activity of ABCB1/Abcb1. ABCG2/Abcg2 is also a major transporter present in most pharmacologically important barriers. However, interaction of ivermectin with Abcg2 shows species specificity and in many studies was confounded by the masking effect of ABCB1/Abcb1. In this study using cellular and membrane assays we show that ivermectin displays a high-affinity interaction with human ABCG2 with IC(50) values in the 1-1.5  µM range. This interaction may have implications in human ABCG2-mediated drug-drug interactions of ivermectin.
    Full-text · Article · Jan 2011 · Journal of Pharmaceutical Sciences

  • No preview · Article · Dec 2010 · ChemInform

  • No preview · Article · Sep 2010 · ChemInform
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    No preview · Article · Jan 2010 · ChemInform
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    ABSTRACT: The pharmacokinetics of sulfasalazine, an anti-inflammatory drug is influenced by ATP-binding cassette G2 (ABCG2) (breast cancer resistance protein (BCRP), mitoxantrone resistance protein (MXR)) both in vitro and clinically. Due to its low passive permeability, the intracellular concentration of sulfasalazine is dependent on uptake transporters, rendering the characterization of transporter specific interactions in cell based experimental systems difficult. Applying membrane assays a detailed kinetic analysis of sulfasalazine ABCG2 interaction was conducted and Km values of 0.70 +/- 0.03 microM and 0.66 +/- 0.08 microM were obtained at pH 7.0 and pH 5.5, respectively.
    No preview · Article · Apr 2009 · Biological & Pharmaceutical Bulletin
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    ABSTRACT: Succinate (SUC), a citrate (CIT) cycle intermediate, and carbenoxolone (CBX), a gap junction inhibitor, were shown to displace [3H]gamma-hydroxybutyrate ([3H]GHB), which is specifically bound to sites present in synaptic membrane subcellular fractions of the rat forebrain and the human nucleus accumbens. Elaboration on previous work revealed that acidic pH-induced specific binding of [3H]SUC occurs, and it has been shown to have a biphasic displacement profile distinguishing high-affinity (K(i,SUC) = 9.1 +/- 1.7 microM) and low-affinity (K(i,SUC) = 15 +/- 7 mM) binding. Both high- and low- affinity sites were characterized by the binding of GHB (K(i,GHB) = 3.9 +/- 0.5 microM and K(i,GHB) = 5.0 +/- 2.0 mM) and lactate (LAC; K(i,LAC) = 3.9 +/- 0.5 microM and K(i,LAC) = 7.7 +/- 0.9 mM). Ligands, including the hemiester ethyl-hemi-SUC, and the gap junction inhibitors flufenamate, CBX, and the GHB binding site-selective NCS-382 interacted with the high-affinity site (in microM: K(i,EHS) = 17 +/- 5, K(i,FFA) = 24 +/- 13, K(i,CBX) = 28 +/- 9, K(i,NCS-382) = 0.8 +/- 0.1 microM). Binding of the Na+,K+-ATPase inhibitor ouabain, the proton-coupled monocarboxylate transporter (MCT)-specific alpha-cyano-hydroxycinnamic acid (CHC), and CIT characterized the low-affinity SUC binding site (in mM: K(i,ouabain) = 0.13 +/- 0.05, K(i,CHC) = 0.32 +/- 0.07, K(i,CIT) = 0.79 +/- 0.20). All tested compounds inhibited [3H]SUC binding in the human nucleus accumbens and had K(i) values similar to those observed in the rat forebrain. The binding process can clearly be recognized as different from synaptic and mitochondrial uptake or astrocytic release of SUC, GHB, and/or CIT by its unique GHB selectivity. The transient decrease of extracellular SUC observed during epileptiform activity suggested that the function of the synaptic target recognizing protonated succinate monocarboxylate may vary under different (patho)physiological conditions. Furthermore, we put forward a hypothesis on the synaptic activity-regulated signaling between astrocytes and neurons via SUC protonation.
    Full-text · Article · May 2008 · Journal of Neuroscience Research
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    ABSTRACT: Extensive chromatographic purification of the alkaloid fraction of Aconitum vulparia Rchb. led to the isolation of a new norditerpene alkaloid, vulparine (1), besides the known compounds septentriodine (2), finetiadine (3), anthranoyllycoctonine (4), Af-methyl-N-deethyllycoctonine (5) and delectinine (6). The structure of the new compound was determined by means of HRMS, ID and 2D NMR spectroscopy. Detailed NMR studies, including 1H-1H COSY, NOESY, HSQC and HMBC experiments, resulted in complete and unambiguous 1H chemical shift assignments for 2 and 6, and revision of some 13C NMR data. Compounds 1-4 were evaluated for their cytotoxic activities, and 1, 3 and 4 were found to exhibit marginal cell growth inhibitory activity against breast adenocarcinoma (MCF-7) and cervix adenocarcinoma (HeLa) cells.
    Full-text · Article · May 2007 · ChemInform
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    ABSTRACT: From the petroleum ether extract of the rhizomes of Tamus communis, the 7-hydroxy-2,3,4,8-tetramethoxyphenanthrene (1) was isolated, together with the known 2,3,4-trimethoxy-7,8-methylenedioxyphenanthrene (2), 3-hydroxy-2,4,-dimethoxy-7,8-methylenedioxyphenanthrene (3), 2-hydroxy-3,5,7-trimethoxyphenanthrene (4) and 2-hydroxy-3,5,7-trimethoxy-9,10-dihydrophenanthrene (5), through cytotoxic assay guidance. The structures were determined by means of HREIMS, (1)H NMR, JMOD and NOESY experiments. The cytotoxic effects of the isolated compounds were tested on cervix adenocarcinoma (HeLa) cells, with the MTT assay. The results demonstrated that, with the exception of 2, all these compounds displayed pronounced cytotoxic activity; especially 1 and 3 exhibited significant cell growth inhibitory effects, with IC(50)=8.52+/-0.70 and 3.64+/-0.12 microM, respectively.
    No preview · Article · Apr 2007 · Phytochemistry
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    ABSTRACT: The aglycones of the antibiotics eremomycin, vancomycin and ristocetin (3, 4 and 6, respectively) were prepared by deglycosidation of the parent antibiotics with hydrogen fluoride, and complete assignation of their 1H, 13C and 15N spectra was performed. The squaric acid amide esters (11-14), were prepared from dimethyl squarate. The corresponding asymmetric diamides (16-19, 22, 23) were also synthesized using 4-phenylbenzylamine and triglycine. The advantage of the method is the high regioselectivity and that no protecting group strategy is required. Electrospray mass spectroscopic method was elaborated for the determination of the site of substitution of the modified antibiotics. The antibacterial activity of the prepared compounds is discussed in detail.
    Full-text · Article · Oct 2006 · The Journal of Antibiotics
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    ABSTRACT: Due to cholestasis or adverse drug effects, the excretion of bilirubin conjugates can decrease; therefore, the level of bilirubin (B) and bilirubin glucuronides (BGs) increases in the serum with the concomitant shift of bilirubin diversus monoglucuronide (BDG/BMG) equilibrium. The aim of this study was to utilize the collagen-sandwich culture of hepatocytes as an in vitro model for studying B conjugation and canalicular versus sinusoidal disposition of BGs. Canalicular and sinusoidal efflux of BMG and BDG obtained in sandwich-cultured rat primary hepatocytes was compared with that measured in human hepatocyte cultures. The BMG and BDG were separated by high-performance liquid chromatography and identified by mass spectrometry. The biliary excretion index (BEI) was estimated by measuring disposition of BGs into standard and Ca(2+), Mg(2+)-free medium. Significantly more BGs were excreted into the canalicular networks than into the medium in 96-h sandwich culture of both human and rat hepatocytes (BEI, 62.5 and 80.6, respectively). The BDG/BMG ratio in the medium versus that in the canalicular networks was 0.55/1.48, which is similar to the serum/bile values (0.6/1.5) observed in vivo by Mesa et al. [Mesa VA, De Vos R, and Fevery J (1997) J Hepatol 27:912-916]. In contrast, the BEI for p-nitrophenol glucuronide was 5.2. The low BEI value is in agreement with empirical observations, which suggest that molecules with low molecular weight are preferably excreted by the kidney. In conclusion, sandwich-cultured primary hepatocytes provide a useful in vitro method to differentiate between sinusoidal and canalicular disposition of BGs. Since the normal BDG/BMG ratio changes in hyperbilirubinemia, this model could be used to predict drug effects leading to hyperbilirubinemia.
    No preview · Article · Oct 2005 · Drug Metabolism and Disposition

Publication Stats

388 Citations
80.09 Total Impact Points

Institutions

  • 2000-2013
    • Hungarian Academy of Sciences
      • • Institute of Molecular Pharmacology
      • • Department of Neurochemistry
      • • Institute of Biochemistry
      Budapeŝto, Budapest, Hungary
  • 2002-2007
    • University of Szeged
      • Department of Pharmacognosy
      Algyő, Csongrád, Hungary
    • Budapest University of Technology and Economics
      • Department of Organic Chemistry and Technology
      Budapest, Budapest fovaros, Hungary