Peroxidase-catalyzed O-demethylation reactions. Quinone-imine formation from 9-methoxyellipticine derivatives.
Despite numerous reports on the N-demethylation reactions catalyzed by peroxidases, to our knowledge, O-demethylation reactions with the same enzymes seem to be still a questionable matter. Unexpectedly, a peroxidase system (horseradish peroxidase and hydrogen peroxide) is able to effect the O-demethylation of the cytotoxic agents 9-methoxyellipticine and N2-methyl-9-methoxyellipticinium acetate. The reaction leads directly to the formation of the corresponding quinone-imine derivatives with the concomitant formation of one molecule of methanol per molecule of methoxy compound. One hydrogen peroxide molecule is consumed during the process. Experiments in H218O-enriched water clearly indicate that 18O is nearly quantitatively incorporated in the carbonyl group of the generated quinone-imine compound with the concomitant elimination of the methoxy group as methanol. So this peroxidase-catalyzed apparent O-demethylation in fact implies an oxidative demethoxylation step. This enzymatic reaction exhibits normal Michaelis-Menten saturation kinetics. Like the 9-hydroxylated ellipticines, both the 9-methoxylated ellipticines show a good affinity for the peroxidase itself (Km approximately 10 microM) but are slowly transformed to the corresponding quinone-imines. The Vmax values for methoxylated ellipticines are 10(-1)-10(-3) lower than those for hydroxylated compounds. This new route for the in vitro formation of electrophilic derivatives from the cytotoxic 9-methoxyellipticine and N2-methyl-9-methoxyellipticinium might be considered as a novel possible metabolic pathway for these drugs, especially if we bear in mind the "bio-oxidative alkylation" process previously described for at least one of the corresponding hydroxylated ellipticine derivatives (see Bernadou, J., Meunier, B., Meunier, G., Auclair, C., and Paoletti, C. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 1297-1301; and Monsarrat, B., Maftouh, M., Meunier, G., Dugué, B., Bernadou, J., Armand, J. P., Picard-Fraire, C., Meunier, B., and Paoletti, C. (1983) Biochem. Pharmacol. 32, 3887-3890).
D000470:Alkaloids / Q000378:metabolism*; D004611:Ellipticines / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D006735:Horseradish Peroxidase / Q000378:metabolism*; D007097:Imines; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D010544:Peroxidases / Q000378:metabolism*; D011809:Quinones; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000470:Alkaloids; D004611:Ellipticines; D007097:Imines; D011809:Quinones; D006735:Horseradish Peroxidase; D010544:Peroxidases; C001729:9-methoxyellipticine