Oxidation pattern of the anticancer drug ellipticine by hepatic microsomes - similarity between human and rat systems
Language English Country Slovakia Media print
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
17197724
Knihovny.cz E-resources
- MeSH
- DNA Adducts metabolism MeSH
- Antineoplastic Agents metabolism MeSH
- Species Specificity MeSH
- Ellipticines metabolism MeSH
- Hydroxylation MeSH
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Enzyme Inhibitors pharmacology MeSH
- Microsomes, Liver drug effects metabolism MeSH
- Rabbits MeSH
- Rats MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Oxidation-Reduction MeSH
- Rats, Wistar MeSH
- Cytochrome P-450 Enzyme System metabolism MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- DNA Adducts MeSH
- Antineoplastic Agents MeSH
- Ellipticines MeSH
- ellipticine MeSH Browser
- Cytochrome P-450 Enzyme Inhibitors MeSH
- Enzyme Inhibitors MeSH
- Cytochrome P-450 Enzyme System MeSH
Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of DNA adducts mediated by cytochrome P450 (CYP). We investigated the ability of CYP enzymes in rat, rabbit and human hepatic microsomes to oxidize ellipticine and evaluated suitable animal models mimicking its oxidation in humans. Ellipticine is oxidized by microsomes of all species to 7-hydroxy-, 9-hydroxy-, 12-hydroxy-, 13-hydroxyellipticine and ellipticine N(2)-oxide. However, only rat microsomes generated the pattern of ellipticine metabolites reproducing that formed by human microsomes. While rabbit microsomes favored the production of ellipticine N(2)-oxide, human and rat microsomes predominantly formed 13-hydroxyellipticine. The species difference in expression and catalytic activities of individual CYPs in livers are the cause of these metabolic differences. Formation of 7-hydroxy- and 9-hydroxyellipticine was attributable to CYP1A in microsomes of all species. However, production of 13-hydroxy-, 12-hydroxyellipticine and ellipticine N(2)-oxide, the metabolites generating DNA adducts, was attributable to the orthologous CYPs only in rats and humans. CYP3A predominantly generates these metabolites in rat and human microsomes, while CYP2C3 activity prevails in microsomes of rabbits. The results underline the suitability of rat species as a model to evaluate human susceptibility to ellipticine.
