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Your search keyword '"Commandeur, Jan N.M."' showing total 193 results
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193 results on '"Commandeur, Jan N.M."'

21. Online biochemical detection of glutathione-S-transferase P1-specific inhibitors in complex mixtures

Author

Kool, Jeroen, Eggink, Mark, Van Rossum, Huub, Van Liempd, Sebastiaan M., Van Elswijk, Danny A., Irth, Hubertus, Commandeur, Jan N.M., Meerman, John H.N., and Vermeulen, Nico P.E.

Subjects
Glutathione transferase -- Research -- Usage, High resolution spectroscopy -- Usage -- Research, Affinity labeling -- Research -- Usage, Biological sciences, Usage, Research
Abstract

A high-resolution screening (HRS) technology is described, which couples 2 parallel enzyme affinity detection (EAD) systems for substrates and inhibitors of rat cytosolic glutathione-S-transferases (cGSTs) and purified human GST P1 [...]

Published
2007

24. Development of a novel cytochrome P450 bioaffinity detection system coupled online to gradient reversed-phase high-performance liquid chromatography

Author

Kool, Jeroen, van Liempd, Sebastiaan M., Ramautar, Rawi, Schenk, Tim, Meerman, John H.N., Irth, Hubertus, Commandeur, Jan N.M., and Vermeulen, Nico P.E.

Subjects
High resolution spectroscopy -- Analysis -- Research, Liquid chromatography -- Analysis -- Research, Cytochrome P-450 -- Research -- Analysis, Biological sciences, Analysis, Research
Abstract

A high-resolution screening platform, coupling online affinity detection for mammalian cytochrome P450s (Cyt P450s) to gradient reversed-phase high-performance liquid chromatography (HPLC), is described. To this end, the online Cyt P450 [...]

Published
2005

28. Characterization of kinetics of human cytochrome P450s involved in bioactivation of flucloxacillin: inhibition of CYP3A-catalysed hydroxylation by sulfaphenazole

Author

Dekker, Stefan J., Dohmen, Floor, Vermeulen, Nico P.E., Commandeur, Jan N.M., Physical Chemistry, AIMMS, Molecular and Computational Toxicology, and Chemistry and Pharmaceutical Sciences

Subjects
Kinetics, Cytochrome P-450 Enzyme System, Molecular Structure, SDG 3 - Good Health and Well-being, Sulfaphenazole, Biocatalysis, polycyclic compounds, Humans, Hydroxylation, Research Papers, Floxacillin, Research Paper
Abstract

Background and Purpose: The aim of this study was to characterize the human cytochrome P450s (CYPs) involved in oxidative bioactivation of flucloxacillin to 5-hydroxymethyl flucloxacillin, a metabolite with high cytotoxicity towards biliary epithelial cells. Experimental Approach: The CYPs involved in hydroxylation of flucloxacillin were characterized using recombinant human CYPs, pooled liver microsomes in the presence of CYP-specific inhibitors and by correlation analysis using a panel of liver microsomes from 16 donors. Key Results: Recombinant CYPs showing the highest specific activity were CYP3A4, CYP3A7 and to lower extent CYP2C9 and CTP2C8. Michaelis–Menten enzyme kinetics were determined for pooled human liver microsomes, recombinant CYP3A4, CYP3A7 and CYP2C9. Surprisingly, sulfaphenazole appeared to be a potent inhibitor of 5′-hydroxylation of flucloxacillin by both recombinant CYP3A4 and CYP3A7. Conclusions and Implications: The combined results show that the 5′-hydroxylation of flucloxacillin is primarily catalysed by CYP3A4, CYP3A7 and CYP2C9. The large variability of the hepatic expression of these enzymes could affect the formation of 5′-hydroxymethyl flucloxacillin, which may determine the differences in susceptibility to flucloxacillin-induced liver injury. Additionally, the strong inhibition in CYP3A-catalysed flucloxacillin metabolism by sulfaphenazole suggests that unanticipated drug–drug interactions could occur with coadministered drugs.

Published
2019

37. Generic method for the absolute quantification of glutathione S-conjugates: Application to the conjugates of acetaminophen, clozapine and diclofenac

Author

den Braver, Michiel W., Vermeulen, Nico P.E., Commandeur, Jan N.M., den Braver, Michiel W., Vermeulen, Nico P.E., and Commandeur, Jan N.M.

Abstract

Modification of cellular macromolecules by reactive drug metabolites is considered to play an important role in the initiation of tissue injury by many drugs. Detection and identification of reactive intermediates is often performed by analyzing the conjugates formed after trapping by glutathione (GSH). Although sensitivity of modern mass spectrometrical methods is extremely high, absolute quantification of GSH-conjugates is critically dependent on the availability of authentic references. Although 1H NMR is currently the method of choice for quantification of metabolites formed biosynthetically, its intrinsically low sensitivity can be a limiting factor in quantification of GSH-conjugates which generally are formed at low levels. In the present study, a simple but sensitive and generic method for absolute quantification of GSH-conjugates is presented. The method is based on quantitative alkaline hydrolysis of GSH-conjugates and subsequent quantification of glutamic acid and glycine by HPLC after precolumn derivatization with o-phthaldialdehyde/N-acetylcysteine (OPA/NAC). Because of the lower stability of the glycine OPA/NAC-derivate, quantification of the glutamic acid OPA/NAC-derivate appeared most suitable for quantification of GSH-conjugates. The novel method was used to quantify the concentrations of GSH-conjugates of diclofenac, clozapine and acetaminophen and quantification was consistent with 1H NMR, but with a more than 100-fold lower detection limit for absolute quantification.

Published
2017
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44. Inter-individual Variability in Activity of the Major Drug Metabolizing Enzymes in Liver Homogenates of 20 Individuals

Author

Braver-Sewradj, Shalenie P. den, Braver, Michiel W. den, van Dijk, Marc, Zhang, Yongjie, Dekker, Stefan J., Wijaya, Lukas, Vermeulen, Nico P.E., Richert, Lysiane, Commandeur, Jan N.M., and Vos, J. C.

Abstract

Background: Inter-individual variability in hepatic drug metabolizing enzyme (DME) activity is a major contributor to heterogeneity in drug clearance and safety. Accurate data on expression levels and activities of DMEs is an important prerequisite for in vitro-in vivo extrapolation and in silico based predictions. Characterization and assessment of inter-correlations of the major DMEs cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) have been extensively documented, but simultaneous quantification including other major DMEs has been lacking. Objective: Assessment of inter-donor variability and inter-correlations of CYPs, UGTs, sulfotransferases (SULTs), glutathione S-transferases (GSTs), NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH: quinone oxidoreductase 2 (NQO2) in a set of 20 individual liver homogenates. Method: The main drug metabolizing isoforms of CYP and UGT have been reaction phenotype in individual liver microsomes and NQO1, NQO2, GSTT1 and GSTT2 in corresponding cytosol. In addition, we assessed overall SULT activity in liver cytosol using acetaminophen and 7-hydroxycoumarin as non-selective substrates and cytosolic GST activity using the non-selective substrate 1-chloro-2,4-dinitrobenzene (CDNB). Expression of GST isoforms was also assessed. Results and Conclusion: While hepatic NQO1 activity was highly variable, NQO2 activity was more conserved. In addition, we found that of the hepatic GST isoforms, the variation in GSTM3 levels, which is poorly studied, was highest. The majority of significant correlations were found amongst CYP and UGT enzyme activities. The dataset presented provides the absolute quantification of the largest number of hepatic DME activities so far and constitute an essential resource for in silico toxicokinetic and metabolic modelling studies.

Published
2018
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