In vitro mammalian metabolism of the mitosis inhibitor zoxamide and the relationship to its in vitro toxicity.

2.50
Hdl Handle:
http://hdl.handle.net/10146/114672
Title:
In vitro mammalian metabolism of the mitosis inhibitor zoxamide and the relationship to its in vitro toxicity.
Authors:
Oesch, F.; Metzler, M.; Fabian, E.; Kamp, H.; Bernshausen, T.; Damm, G.; Triebel, S.; Dohmer, J.; Landsiedel, R.; Van Ravenzwaay, B.
Abstract:
The in vitro mammalian metabolism of the fungicide zoxamide is related to its in vitro mammalian toxicity. After incubation of zoxamide with rat liver microsomes leading to practically 100% metabolism (mostly hydroxylated zoxamide), the cytotoxicity (methyl thiazole tetrazolium (MTT) test) and the mitosis-inhibiting potential (shown by cell count and by cell cycle analysis) for V79 were not distinguishable from those of zoxamide, demonstrating that the hydroxylation of zoxamide did not change the cytotoxicity or mitosis-inhibiting potential as determined by these assays. After incubation of zoxamide with rat liver S9 predominantly leading to conjugation with glutathione, and after incubation of zoxamide with rat liver slices predominantly leading to the glucuronide of the hydroxylated zoxamide, these activities were eliminated demonstrating that the glutathione conjugate and the glucuronide had lost the activities in these assays due either to no intrinsic potential of these conjugates or to their inability to penetrate the plasma membrane of mammalian cells. It is concluded that the metabolic hydroxylation of zoxamide did not change its activity in the assays used for investigating its influence on cell proliferation, cell cycle and cytotoxicity, while the formation of conjugates with glutathione or glucuronic acid led to the apparent loss of these activities. Thus, with zoxamide as a prototype, it was shown that, in principle, mammalian metabolism and its relationship to mammalian detoxication of fungicidal mitosis inhibitors may be reasonably anticipated from in vitro studies. In addition, the results provide a rational for the observed absence of typically mitosis inhibition-associated toxicities of zoxamide in mammals in vivo.
Citation:
Xenobiotica 2010, 40 (1):72-82
Journal:
Xenobiotica; the fate of foreign compounds in biological systems
Issue Date:
Jan-2010
URI:
http://hdl.handle.net/10146/114672
DOI:
10.3109/00498250903353464
PubMed ID:
20001673
Additional Links:
http://informahealthcare.com/doi/abs/10.3109/00498250903353464
Type:
Article
Language:
en
ISSN:
1366-5928
Sponsors:
The support by the European Union Network of Excellence Environmental Cancer, Nutrition and Individual Susceptibility (ECNIS) operating within the European Union 6th Framework Programme, Priority 5: ‘Food Quality and Safety’ (Contract Number 513943) is gratefully acknowledged.
Appears in Collections:
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Full metadata record

DC FieldValue Language
dc.contributor.authorOesch, F.en
dc.contributor.authorMetzler, M.en
dc.contributor.authorFabian, E.en
dc.contributor.authorKamp, H.en
dc.contributor.authorBernshausen, T.en
dc.contributor.authorDamm, G.en
dc.contributor.authorTriebel, S.en
dc.contributor.authorDohmer, J.en
dc.contributor.authorLandsiedel, R.en
dc.contributor.authorVan Ravenzwaay, B.en
dc.date.accessioned2010-11-04T10:28:35Z-
dc.date.available2010-11-04T10:28:35Z-
dc.date.issued2010-01-
dc.identifier.citationXenobiotica 2010, 40 (1):72-82en
dc.identifier.issn1366-5928-
dc.identifier.pmid20001673-
dc.identifier.doi10.3109/00498250903353464-
dc.identifier.urihttp://hdl.handle.net/10146/114672-
dc.description.abstractThe in vitro mammalian metabolism of the fungicide zoxamide is related to its in vitro mammalian toxicity. After incubation of zoxamide with rat liver microsomes leading to practically 100% metabolism (mostly hydroxylated zoxamide), the cytotoxicity (methyl thiazole tetrazolium (MTT) test) and the mitosis-inhibiting potential (shown by cell count and by cell cycle analysis) for V79 were not distinguishable from those of zoxamide, demonstrating that the hydroxylation of zoxamide did not change the cytotoxicity or mitosis-inhibiting potential as determined by these assays. After incubation of zoxamide with rat liver S9 predominantly leading to conjugation with glutathione, and after incubation of zoxamide with rat liver slices predominantly leading to the glucuronide of the hydroxylated zoxamide, these activities were eliminated demonstrating that the glutathione conjugate and the glucuronide had lost the activities in these assays due either to no intrinsic potential of these conjugates or to their inability to penetrate the plasma membrane of mammalian cells. It is concluded that the metabolic hydroxylation of zoxamide did not change its activity in the assays used for investigating its influence on cell proliferation, cell cycle and cytotoxicity, while the formation of conjugates with glutathione or glucuronic acid led to the apparent loss of these activities. Thus, with zoxamide as a prototype, it was shown that, in principle, mammalian metabolism and its relationship to mammalian detoxication of fungicidal mitosis inhibitors may be reasonably anticipated from in vitro studies. In addition, the results provide a rational for the observed absence of typically mitosis inhibition-associated toxicities of zoxamide in mammals in vivo.en
dc.description.sponsorshipThe support by the European Union Network of Excellence Environmental Cancer, Nutrition and Individual Susceptibility (ECNIS) operating within the European Union 6th Framework Programme, Priority 5: ‘Food Quality and Safety’ (Contract Number 513943) is gratefully acknowledged.en
dc.language.isoenen
dc.relation.urlhttp://informahealthcare.com/doi/abs/10.3109/00498250903353464en
dc.subjectFungicidesen
dc.subjectAmidesen
dc.subjectToxicityen
dc.subjectLiveren
dc.subjectMicrosomesen
dc.subjectCytochrome P-450 Enzyme Systemen
dc.subjectAnimalsen
dc.subjectHumansen
dc.subject.meshAmides-
dc.subject.meshAnimals-
dc.subject.meshCell Line-
dc.subject.meshCytochrome P-450 Enzyme System-
dc.subject.meshFungicides, Industrial-
dc.subject.meshHumans-
dc.subject.meshHydroxylation-
dc.subject.meshLiver-
dc.subject.meshMicrosomes, Liver-
dc.subject.meshMitosis-
dc.subject.meshRats-
dc.subject.meshTransfection-
dc.titleIn vitro mammalian metabolism of the mitosis inhibitor zoxamide and the relationship to its in vitro toxicity.en
dc.typeArticleen
dc.identifier.journalXenobiotica; the fate of foreign compounds in biological systemsen
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