Ellipticine is an antineoplastic agent whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II, and formation of covalent DNA adducts mediated by cytochromes P450 (P450s) and peroxidases. Here, this drug was found to induce CYP1A1 and/or 1A2 enzymes and their enzymatic activities in livers, lungs, and kidneys of rats treated (i.p.) with ellipticine. The induction is transient. In the absence of repeated administration of ellipticine, the levels and activities of the induced CYP1A decreased almost to the basal level 2 weeks after treatment. The ellipticine-mediated CYP1A induction increases the DNA adduct formation by the compound. When microsomal fractions from livers, kidneys, and lungs of rats treated with ellipticine were incubated with ellipticine, DNA adduct formation, measured by (32)P-postlabeling analysis, was up to 3.8-fold higher in incubations with microsomes from pretreated rats than with controls. The observed stimulation of DNA adduct formation by ellipticine was attributed to induction of CYP1A1 and/or 1A2-mediated increase in ellipticine oxidative activation to 13-hydroxy- and 12-hydroxyellipticine, the metabolites generating two major DNA adducts in human and rat livers. In addition to these metabolites, increased formation of the excretion products 9-hydroxy- and 7-hydroxyellipticine was also observed in microsomes of rats treated with ellipticine. Taken together, these results demonstrate for the first time that by inducing CYP1A1/2, ellipticine increases its own metabolism, leading both to an activation of this drug to reactive species-forming DNA adducts and to detoxication metabolites, thereby modulating to some extent its pharmacological and/or genotoxic potential.
- MeSH
- adukty DNA MeSH
- cytochrom P-450 CYP1A1 biosyntéza genetika MeSH
- cytochrom P-450 CYP1A2 biosyntéza genetika MeSH
- cytochromy MeSH
- elipticiny farmakologie MeSH
- enzymová indukce účinky léků MeSH
- játra metabolismus účinky léků MeSH
- krysa rodu rattus MeSH
- ledviny metabolismus účinky léků MeSH
- messenger RNA metabolismus MeSH
- mikrozomy enzymologie MeSH
- plíce metabolismus účinky léků MeSH
- potkani Wistar MeSH
- protinádorové látky farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- MeSH
- benzopyren * chemie toxicita MeSH
- biotransformace MeSH
- cytochrom P-450 CYP1A1 * farmakokinetika terapeutické užití MeSH
- hepatocyty enzymologie účinky léků MeSH
- jaterní mikrozomy MeSH
- játra metabolismus MeSH
- karcinogeny MeSH
- krysa rodu rattus MeSH
- myši knockoutované MeSH
- NADPH-cytochrom c-reduktasa * MeSH
- polycyklické aromatické uhlovodíky chemie škodlivé účinky toxicita MeSH
- systém (enzymů) cytochromů P-450 farmakokinetika terapeutické užití MeSH
- umlčování genů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- cytochrom P-450 CYP1A1 MeSH
- elipticiny genetika MeSH
- experimenty na zvířatech MeSH
- exprese genu účinky léků MeSH
- farmakologické účinky MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus genetika imunologie metabolismus MeSH
- lidé MeSH
- regulace genové exprese účinky záření MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus genetika imunologie metabolismus MeSH
- lidé MeSH
- zvířata MeSH
Ellipticine is a potent antineoplastic agent, whose mode of action is considered to be based mainly on DNA intercalation and/or inhibition of topoisomerase II. Recently, we found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts. Here, we study the effect of ellipticine on CYP enzymes in rat hepatic microsomes, studying its binding to the enzymes and its potential to inhibit the CYP activities measured with their selective substrates. Although ellipticine was reported to be a selective and strong inhibitor of CYP1A1/2, we found that its inhibitory potential is non-specific. Ellipticine is the most potent inhibitor for CYP3A-dependent 6beta-hydroxylation of progesterone, followed by CYP1A1/2-dependent ethoxyresorufin O-deethylation and CYP2B-mediated pentoxyresorufin O-depentylation. Lower inhibition was detected for 1'-hydroxylation of bufurarol, 21-hydroxylation of progesterone and 6-hydroxylation of chlorzoxazone catalyzed by CYP2D, CYP2C and CYP2E1, respectively. Ellipticine binds to several CYPs of rat hepatic microsomes. The binding titration of ellipticine typically give reverse type I spectrum with CYPs in rat hepatic microsomes. The results indicate that inhibition of CYPs by ellipticine cannot be explained only by its differential potency to bind to individual CYPs.
- MeSH
- elipticiny farmakologie MeSH
- inhibitory cytochromu P450 MeSH
- inhibitory enzymů farmakologie MeSH
- jaterní mikrozomy enzymologie MeSH
- krysa rodu rattus MeSH
- protinádorové látky farmakologie MeSH
- systém (enzymů) cytochromů P-450 MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
