In vitro mammalian metabolism of the mitosis inhibitor zoxamide and the relationship to its in vitro toxicity.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Van Ravenzwaay, B.
MetadataShow full item record
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.
CitationXenobiotica 2010, 40 (1):72-82
SponsorsThe 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.
- NTP technical report on the toxicity and metabolism studies of chloral hydrate (CAS No. 302-17-0). Administered by gavage to F344/N rats and B6C3F1 mice.
- Authors: Beland FA
- Issue date: 1999 Aug
- Studies on the cytochrome P450 (CYP)-mediated metabolic properties of miocamycin: evaluation of the possibility of a metabolic intermediate complex formation with CYP, and identification of the human CYP isoforms.
- Authors: Kasahara M, Suzuki H, Komiya I
- Issue date: 2000 Apr
- Induction and inhibition of cytochrome P450-dependent monooxygenases of rats by fungicide bitertanol.
- Authors: Chan PK, Lu SY, Liao JW, Wei CF, Tsai Y, Ueng TH
- Issue date: 2006 Dec
- In vivo modulation of alternative pathways of P-450-catalyzed cyclophosphamide metabolism: impact on pharmacokinetics and antitumor activity.
- Authors: Yu LJ, Drewes P, Gustafsson K, Brain EG, Hecht JE, Waxman DJ
- Issue date: 1999 Mar
- Comparison of human and rat metabolism of molinate in liver microsomes and slices.
- Authors: Jewell WT, Miller MG
- Issue date: 1999 Jul