Oxidation pattern of the anticancer drug ellipticine by hepatic microsomes - similarity between human and rat systems.
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.
Stiborová
M
M
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic. stiborov@natur.cuni.cz
Borek-Dohalská
L
L
Aimová
D
D
Kotrbová
V
V
Kukacková
K
K
Janouchová
K
K
Rupertová
M
M
Ryslavá
H
H
Hudecek
J
J
Frei
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004611:Ellipticines / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D018736:DNA Adducts; D004611:Ellipticines; D004791:Enzyme Inhibitors; C034192:ellipticine; D003577:Cytochrome P-450 Enzyme System