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39 results on '"Vermeulen N"'

16. Inhibition of human glutathione S-transferases by curcumin and analogues.

Author

Appiah-Opong, R., Commandeur, J. N. M., Istyastono, E., Bogaards, J. J., and Vermeulen, N. P. E.

Subjects
GLUTATHIONE transferase, CONTACT inhibition, ELECTROPHILES, ISOENZYMES, QSAR models, VAN der Waals forces
Abstract

Glutathione S-transferases (GSTs) are important phase II drug-metabolizing enzymes that play a major role in protecting cells from the toxic insults of electrophilic compounds. Curcumin, a promising chemotherapeutic agent, inhibits human GSTA1-1, GSTM1-1, and GSTP1-1 isoenzymes. In the present study, the effect of three series of curcumin analogues, 2,6-dibenzylidenecyclohexanone (A series), 2,5-dibenzylidenecyclopentanone (B series), and 1,4-pentadiene-3-one (C series) substituted analogues (n = 34), on these three human GST isoenzymes, and on human and rat liver cytosolic GSTs, was investigated using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate. Most of the 34 curcumin analogues showed less potent inhibitory activities towards GSTA1-1, GSTM1-1, and GSTP1-1 than the parent curcumin. Compounds B14 and C10 were the most potent inhibitors of GSTA1-1 and human liver cytosolic GSTs, with IC50 values of 0.2-0.6 μM. The most potent inhibitors of GSTM1-1 were C1, C3 and C10, with IC50 values of 0.2-0.7 μM. Similarly, GSTP1-1 was predominantly strongly inhibited by compounds of the C series C0, C1, C2 C10 and A0, with IC50 values of 0.4-4.6 μM. Compounds in the B series showed no significant inhibition of GSTP1-1. Molecular Operating Environment (MOE) program-based quantitative structure-activity relationship (QSAR) analyses have also suggested the relevance of Van der Waals surface area and compound lipophilicity factors for the inhibition of GSTA1-1 and GSTM1-1 and partial charge factors for GSTP1-1. These results may be useful in the design and synthesis of curcumin analogues with either more or less potency for GST inhibition. [ABSTRACT FROM AUTHOR]

Published
2009
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18. Metabolism of N -substituted 7-methoxy-4-(aminomethyl) -coumarins by cytochrome P450 2D6 mutants and the indication of additional substrate interaction points.

Author

Keizers, P. H. J., Van Dijk, B. R., De Graaf, C., Van Vugt-Lussenburg, B. M. A., Vermeulen, N. P. E., and Commandeur, J. N. M.

Subjects
COUMARINS, CYTOCHROME P-450, METABOLISM, HUMAN chromosomes, BINDING sites, MUTAGENESIS
Abstract

Previous studies have shown the critical roles residues F120 and F483 play in the oxidative metabolism of 7-methoxy-4-(aminomethyl)-coumarin (MAMC) by cytochrome P450 2D6 (CYP2D6). In the present study, a series of N -alkyl-7-methoxy-4-(aminomethyl)-coumarins (MAMC analogues) were used as substrates for the F120A and F483A mutants in order to probe the CYP2D6 active site. The F120A and F483A mutants of CYP2D6 displayed significant activity towards the MAMC analogues. Automated docking studies of the MAMC analogues in a CYP2D6 homology model suggested a distal hydrophobic active site binding cleft for the substrate N -alkyl chains, consisting of the residues L213 and V308. [ABSTRACT FROM AUTHOR]

Published
2006
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20. The epoxide-diol pathway in the metabolism of vinylbital in rat and man

Author

Vermeulen, N P, Bakker, B H, Eylers, D, Breimer, D D, Molecular and Computational Toxicology, and AIMMS

Subjects
Pharmacology, Epoxide Hydrolases, Male, Chromatography, Chromatography, Gas, Vinyl Compounds, Health, Toxicology and Mutagenesis, General Medicine, Toxicology, Biochemistry, Gas Chromatography-Mass Spectrometry, Rats, Liver, Gas, Microsomes, Barbiturates, Microsomes, Liver, Journal Article, Animals, Epoxy Compounds, Humans
Abstract

1. In urine of rats given vinylbital (5-vinyl-5-(1'-methylbutyl)barbituric acid) i.p., unchanged vinylbital and its devinylated metabolite, 5-(1'-methylbutyl)barbituric acid, were identified. Rats synthetic 1',2'-epoxyvinylbital excreted the same compound as a major metabolite. No unchanged epoxide, nor 1',2'-dihydroxyvinylbital, could be identified in the urine of rats treated with vinylbital or its epoxide. 2. Attempts to synthesize 1',2'-dihydroxyvinylbital from 1',2'-epoxyvinylbital by acidic hydrolysis revealed that this possible metabolite decomposes readily to 5-(1'-methylbutyl)barbituric acid by a 'retro-aldol type' reaction. 3. In rat liver microsomal preparation 1',2'-epoxyvinylbital is readily hydrated by epoxide hydratase, but this reaction is almost completely inhibited by 0.8 mM 1,1,1-trichloropropene-2,3-oxide (TCPO). This finding and the identification of 5-(1'-methylbutyl)barbituric acid as end-product of this enzyme reaction provides further evidence for the existence of an epoxide-diol pathway in the metabolism of vinylbital. 4. Vinylbital and its devinylated metabolite are excreted in 36 h urine of rats treated with vinylbital, to an extent of 0.6 +/- 1.7% of the dose (n = 5), respectively. Upon administration of 1',2-epoxyvinylbital, 59.8 +/- 14.2% of the dose (n = 5) was excreted as 5-(1'-methylbutyl)barbituric acid. 5. In 60 h urine of three human volunteers who had taken 150 mg of vinylbital orally, 2.6 +/- 1.7% of the dose was excreted as vinylbitaland 11.0 +/- 4.1% as 5-(1'-methylbutyl) barbituric acid, illustrating that also in humans the epoxide-diol pathway plays a role in the metabolism of vinylbital.

Published
1980

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