Cytochrome b shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy

Věra Kotrbová (1) , Barbora Mrázová (1) , Michaela Moserová (1) , Václav Martínek (1) , Petr Hodek (1) , Jiří Hudeček (1) , Eva Frei (2) , Marie Stiborová (1)

1 Faculty of Science
2 Division of Preventive Oncology

Ellipticine is a pro-drug, whose activation is dependent on its oxidation by cytochromes P450 (CYP) and peroxidases. Cytochrome b alters the ratio of ellipticine metabolites formed by isolated reconstituted CYP1A1 and 1A2, favoring formation of 12-hydroxy- and 13-hydroxyellipticine metabolites implicated in ellipticine-DNA adduct formation, at the expense of 9-hydroxy- and 7-hydroxyellipticine that are detoxication products. Cytochrome b enhances the production of 12-hydroxy and 13-hydroxyellipticine. The change in metabolite ratio results in an increased formation of covalent ellipticine-DNA adducts, one of the DNA-damaging mechanisms of ellipticine antitumor action. This finding explains previous apparent discrepancies found with isolated enzymes and , where CYP1A enzymatic activation correlated with ellipticine-DNA-adduct levels while isolated CYP1A1 or 1A2 in reconstituted systems were much less effective than CYP3A4. The effect of cytochrome b might be even more pronounced , since, as we show here, ellipticine increases levels of cytochrome b in rat liver. Our results demonstrate that both the native 3D structure of cytochrome b and the presence of the heme as an electron transfer agent in this protein enable a shift in ellipticine metabolites formed by CYP1A1/2.

Mots clés: CYP1A1/2; cytochrome b; ellipticine; modulation; activation

Domaines: Pharmacologie

Věra Kotrbová, Barbora Mrázová, Michaela Moserová, Václav Martínek, Petr Hodek, et al.. Cytochrome b shifts oxidation of the anticancer drug ellipticine by cytochromes P450 1A1 and 1A2 from its detoxication to activation, thereby modulating its pharmacological efficacy. Biochemical Pharmacology, 2011, 82 (6), pp.669. ⟨10.1016/j.bcp.2011.06.003⟩. ⟨hal-00722844⟩