monooxygenase
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- MeSH
- játra enzymologie účinky léků MeSH
- krysa rodu rattus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
Trimethylaminuria (TMAuria), the excessive urinary excretion of the odorous trimethylamine (TMA), accompanies elimination of TMA in sweat and corresponding "fish-odor" syndrome. TMA was oxidized in vitro in rat liver microsomes from male Sprague-Dawley rats to TMA N-oxide and N-demethylated to dimethylamine (DMA). Both reactions were inhibited to 1-3% of normal activity by preincubation of microsomes without NADPH-generating system at 37 degrees C for 10 minutes indicating the FAD-containing monooxygenase-catalyzed reactions. On the other hand, the reactions were not inhibited by gas phase containing up to 80% carbon monoxide/20% oxygen mixture. The results are compatible with the hypothesis that in rat liver microsomes the N-oxygenation and N-demethylation of TMA are catalyzed only or predominantly by FAD-containing monooxygenases, and the cytochrome P-450 monooxygenases play a negligible, if any, role.
- MeSH
- chromatografie plynová MeSH
- dealkylace MeSH
- flavinadenindinukleotid * metabolismus MeSH
- inbrední kmeny potkanů MeSH
- jaterní mikrozomy * enzymologie MeSH
- krysa rodu rattus MeSH
- methylaminy * metabolismus MeSH
- NAD metabolismus MeSH
- NADP metabolismus MeSH
- oxidace-redukce MeSH
- oxygenasy se smíšenou funkcí * metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- jaterní mikrozomy fyziologie účinky léků MeSH
- krysa rodu rattus MeSH
- morfin MeSH
- systém (enzymů) cytochromů P-450 analýza MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.
- MeSH
- chinazoliny metabolismus MeSH
- jaterní mikrozomy MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- oxidace-redukce MeSH
- oxygenasy metabolismus MeSH
- piperidiny metabolismus MeSH
- protinádorové látky metabolismus MeSH
- systém (enzymů) cytochromů P-450 metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- buněčný cyklus fyziologie MeSH
- fibrosarkom veterinární MeSH
- finanční podpora výzkumu jako téma MeSH
- inhibitory enzymů farmakologie MeSH
- kyselina arachidonová antagonisté a inhibitory metabolismus MeSH
- lipoxygenasa farmakologie MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- systém (enzymů) cytochromů P-450 farmakologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
