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AR Goeptar, JM Te Koppele, EK Lamme, JM Pique and NP Vermeulen
Leiden/Amsterdam Center for Drug Research, Division of Molecular Toxicology, Vrije Universiteit, The Netherlands.
The role of cytochrome P450 (CYP) in the one-electron reductive bioactivation of Adriamycin (ADR) (doxorubicin) was investigated in subcellular fractions of the rat liver. The rate of one-electron reduction of ADR to its semiquinone free radical (ADRSQ), measured by ESR, was 5-fold greater with phenobarbital (PB)-induced (PB microsomes) than with beta-naphthoflavone (beta NF)-induced (beta NF microsomes) rat liver microsomes under anaerobic conditions. ADRSQ formation was inhibited by SK&F 525-A and metyrapone (MP) in PB microsomes but was not significantly inhibited in beta NF microsomes. Under aerobic conditions, the formation of ADRSQ from ADR was diminished in microsomal incubations and concomitant reduction of molecular oxygen occurred instead. Whereas ADR-induced H2O2 formation in PB microsomes was strongly inhibited by SK&F 525-A and MP, only a slight inhibition was observed with 2-ethylnylnaphthalene and 1-ethynylpyrene in beta NF microsomes. In addition, MP produced strong inhibition of ADR- stimulated lipid peroxidation in PB microsomes, compared with beta NF microsomes. The idea that CYP2B1 was involved in the one-electron reduction of ADR in PB microsomes and in reconstituted systems of purified CYP2B1 and purified NADPH-CYP reductase (RED) under anaerobic conditions could be concluded from inhibition studies using SK&F 525-A and antibodies (KO1) against CYP2B enzymes. Moreover, it was calculated from reconstitution experiments using varying amounts of purified CYP2B1 and purified RED that the contribution of CYP2B1 to the one- electron reduction of ADR was similar to that of RED alone.
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