The biotransformation of isoprene and the two isoprene monoepoxides by human cytochrome P450 enzymes, compared to mouse and rat liver microsomes

Bogaards, J.J.P.; Venekamp, J.C.; Bladeren, P.J. van

doi:10.1016/s0009-2797(96)03741-6

Cited by 28 publications

(25 citation statements)

References 20 publications

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“…6B) was observed between 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity and levels of CYP2B6 apoprotein. The lower correlation between 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity and CYP2B6 apoprotein levels may be attributable to the observation that even in the presence of ␣-naphthoflavone to inhibit CYP1A2 activity, this substrate is not specific for CYP2B6, being also metabolized by other P450 enzymes in human liver (Bogaards et al, 1996;Code et al, 1997).…”

Section: Fig 1 Effect Of Treatment Of Human Liver Slices With Bnf mentioning

confidence: 99%

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Edwards¹,

Price²,

Watts³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Precision-cut human liver slices obtained from 11 donors were cultured for 72 h in a defined medium (serum free Williams' medium E) supplemented with 0.1 M insulin and 0.1 M dexamethasone (DEX). Liver slices were treated with 50 M concentrations of ␤ -naphthoflavone (BNF), lansoprazole, rifampicin (RIF), DEX and methylclofenapate and 500 M sodium phenobarbital (NaPB). The relative apoprotein levels of 12 cytochrome P450 (P450) enzymes were determined in liver slice microsomes using a panel of antipeptide antibodies. Treatment with BNF significantly induced mean levels of CYP1A2 apoprotein to 160% of levels in 72-h control (no test compound) human liver slice microsomes. NaPB significantly induced levels of CYP3A4 apoprotein to 255% of control and RIF significantly induced levels of CYP2C19 and CYP3A4 apoproteins to 265 and 330% of control, respectively. In addition, treatment with RIF increased levels of CYP2A6 apoprotein to 205% of control, and treatment with both NaPB and RIF increased levels of CYP2B6 apoprotein to 370 and 615% of control, respectively. However, these increases were not statistically significant, owing to a variable response between liver slice preparations from different subjects, this being apparent for all inducible P450s. In contrast, none of the compounds examined significantly increased levels of CYP2C8, CYP2C9, CYP2D6, CYP2E1, and CYP4A11 apoproteins. Levels of CYP1A1 apoprotein were not detected in any liver slice sample, either before or after treatment with the model inducers. Overall, these results demonstrate the utility of cultured human liver slices for assessing the effects of chemicals on P450 enzymes.

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Section: Fig 1 Effect Of Treatment Of Human Liver Slices With Bnf mentioning

confidence: 99%

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Edwards¹,

Price²,

Watts³

et al. 2003

Drug Metab Dispos

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“…The CID spectrum of M13 suggested that it was an adduct formed by addition of glutathione to the epoxide M3 and this reaction competed with its hydrolysis to give the diol M5. In order to better characterize the formation of epoxide M3, we incubated compound A in rat liver microsomes with or without cyclohexene oxide (1 mM), an inhibitor of microsomal epoxide hydrolases (mEH) (Bogaards et al 1996). In presence of cyclohexene oxide, the steadystate concentration of the epoxide (M3) was increased, and the formation of the hydrolysis product (M5) was reduced (Figure 9).…”

Section: In Vitro Resultsmentioning

confidence: 99%

“…In this case, 1 mM cyclohexene oxide (acetone solution) was added to the incubation mixture (final amount of acetone = 0.2%) (Bogaards et al 1996) using the above conditions. Incubation with rat cDNA-expressed cytochrome P450 isozymes.…”

Section: Introductionmentioning

confidence: 99%

Metabolism-related liabilities of a potent histone deacetylase (HDAC) inhibitor and relevance of the route of administration on its metabolic fate

et al. 2009

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Compound A [1-methyl-N-{(1S)-1-[5-(2-naphthyl)-1H-imidazol-2-yl]-7-oxooctyl}piperidine-4-carboxamide is a potent class I histone deacetylase (HDAC) inhibitor that demonstrated good antiproliferative activity against human tumour cell lines of different origin. This compound showed high in vivo clearance in rats (160 ml min(-1) kg(-1)) due to metabolism. The main metabolite detected in urine after intravenous dosing was characterized as a dihydrohydroxy S-mercapturic acid conjugate. Following oral dosing, however, the mercapturic acid derivative was no longer the main metabolite but the major metabolites were mono- and di-glucuronide conjugates of oxidized species having a mass shift of +34 m/z with respect to the parent. Comparison of plasma concentration after intra-arterial infusion and intravenous infusion and incubation with microsomes from different tissues (liver, kidney, small intestine and lung) in the presence of beta-nicotinamide adenine dinucleotide phosphate (NADPH) indicated that the compound was highly cleared by the lung. Oxidation of the naphthalene moiety was demonstrated to be the cause of the high in vivo clearance of compound A and the potential for bioactivation of this group was flagged.

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“…Alle Epoxide und Diole liegen als optische Isomeren vor (Chiappe et al 2000;Golding et al 2003). In vitro fand die Oxidation von Isopren zu den Monoepoxiden vorwiegend durch CYP2E1, gefolgt von CYP2B6, statt (Bogaards et al 1996) (Bogaards et al 1996). CYP2E1 führte als einziges Cytochrom-P450-Isoenzym zu nachweisbaren Mengen des Diepoxids.…”

Section: Metabolismusunclassified

“…967 pmol/min und nmol Cytochrom P450 und für Wistar-Ratten 1150 bzw. 1360 pmol/min und nmol Cytochrom P450 (Bogaards et al 1996). Im Vergleich zu Maus und Ratte war die Aktivität der GSH-Transferasen in der mikrosomalen Fraktion aus der Leber des Menschen 25-bis 50-fach niedriger (Bogaards et al 1999).…”

Section: Metabolismusunclassified

Isopren (2‐Methyl‐1,3‐butadien) [MAK Value Documentation in German language, 2009]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 46. Lieferung, Ausgabe 2009 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Endogene Bildung von Isopren Aufnahme, Verteilung, Ausscheidung Metabolismus Hämoglobin‐Addukt‐Bildung Physiologisch‐toxikokinetische Modelle Ableitung eines MAK‐Werts für Isopren Erfahrungen beim Menschen Einmalige Exposition Wiederholte Exposition Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Sonstige Wirkungen Bewertung

show abstract

The biotransformation of isoprene and the two isoprene monoepoxides by human cytochrome P450 enzymes, compared to mouse and rat liver microsomes

Cited by 28 publications

References 20 publications

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Induction of Cytochrome P450 Enzymes in Cultured Precision-Cut Human Liver Slices

Metabolism-related liabilities of a potent histone deacetylase (HDAC) inhibitor and relevance of the route of administration on its metabolic fate

Isopren (2‐Methyl‐1,3‐butadien) [MAK Value Documentation in German language, 2009]

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