Inhibition of drug oxidation and stimulation of NADPH oxidase in vitro by doxorubicin and triferric-doxorubicin.
The electrophilic properties of the quinone-hydroquinone configuration of anthracycline antibiotics suggests a possible influence on cytochrome P-450-mediated mono-oxygenase reactions. Both doxorubicin and triferric-doxorubicin (a derivative in which the quinone groups are blocked with iron) showed a similar dose-dependent inhibition of liver microsomal drug metabolism. A doxorubicin concentration-related stimulation of NADPH oxidase activity was found to be linear but that for triferric-doxorubicin was asymptotic. Neither inhibitor affected the activity of cytochrome c reductase, cytochrome b5 reductase or cytochrome P-450 reductase. However, doxorubicin did potentiate the inhibitory effect of aniline on cytochrome P-450 reductase and on ethylmorphine metabolism. It is concluded that these anthracyclines inhibit drug metabolism in vitro not by their electron-withdrawing potential but in a manner more similar to that described for type II compounds.
D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005290:Ferric Compounds / Q000494:pharmacology; D006591:Hexobarbital / Q000494:pharmacology; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D013268:Stimulation, Chemical
D000627:Aminophenols; D005290:Ferric Compounds; D004364:Pharmaceutical Preparations; D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D009247:NADH, NADPH Oxidoreductases