The Anticancer Drug Ellipticine Induces Cytochromes P450 1A1, 1A2 and 3A, Cytochrome b(5) and NADPH:Cytochrome P450 Oxidoreductase in Rat Liver, Kidney and Lung
Abstract
The antineoplastic alkaloid ellipticine is a prodrug, the pharmacological efficiency of which is dependent on its cytochrome P450 (CYP)- and/or peroxidase-mediated activation in target tissues. Using the Western blotting, we found that this compound increases protein expression of cytochrome b(5), CYP1A1, 1A2, 3A and NADPH: CYP oxidoreductase (POR) in livers, lungs and kidneys of rats treated (i.p.) with ellipticine.
The ellipticine-mediated induction of these enzymes resulted in an increase in their enzymatic activities and ellipticine oxidation to 7-hydroxy-, 9-hydroxy-, 12-hydroxy-and 13-hydroxyellipticine, the metabolites that are both detoxication products (7-hydroxy-, 9-hydroxyellipticine) and metabolites responsible for generation ellipticine-derived DNA adducts (12-hydroxy- and 13-hydroxyellipticine). The results demonstrate that by inducing CYP1A1/2, 3A, POR and cytochrome b(5), ellipticine increases its own metabolism in rats, thereby modulating its own pharmacological and/or genotoxic potential.