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J. Biol. Chem., Vol. 259, Issue 2, 959-966, 01, 1984
SS Pan, PA Andrews, CJ Glover and NR Bachur
Under anaerobic conditions and with proper electron donors, NADPH-
cytochrome P-450 reductase (EC 1.6.2.4) and xanthine oxidase (EC 1.2.3.2)
similarly reductively metabolized mitomycin C. Reversed phase high
performance liquid chromatography was used to separate, detect, and isolate
several metabolites. Three metabolites were identified by mass spectrometry
and thin layer chromatography as 1,2-cis- and trans-
2,7-diamino-1-hydroxymitosene and 2,7-diaminomitosene. Three metabolites
were phosphate-dependent, and two of them were identified to be 1,2-cis-
and trans-2,7-diaminomitosene 1-phosphate. The amounts of the five
identified metabolites generated during the reduction of mitomycin C varied
with pH and nucleophile concentration. At pH 6.5, 2,7-diaminomitosene was
essentially the only metabolite formed, whereas from pH 6.8 to 8.0, trans-
and cis-2,7-diamino-1-hydroxymitosene increased in quantity as
2,7-diaminomitosene decreased. The disappearance of mitomycin C and the
production of metabolites were enzyme and mitomycin C
concentration-dependent. Substrate saturation was not reached for either
enzyme up to 5 mM mitomycin C. Electron paramagnetic resonance studies
demonstrated the formation of mitomycin C radical anion as an intermediate
during enzymatic activation. Our results indicate that either enzyme
catalyzed the initial activation of mitomycin C to a radical anion
intermediate. Subsequent spontaneous reactions, including the elimination
of methanol and the opening of the aziridine ring, generate one active
center at C-1 which facilitates nucleophilic attack. Simultaneous
generation of two reactive centers was not observed. All five primary
metabolites were metabolized further by either flavoenzyme. The secondary
metabolites exhibited similar changes in their absorbance spectra and were
unlike the primary metabolites, suggesting that a second alkylating center
other than C-1 was generated during secondary activation. We propose that
secondary activation of monofunctionally bound mitomycin C is probably a
main route for the bifunctional binding of mitomycin C to macromolecules
and that the cytotoxic actions of mitomycin C result from multiple
metabolic activations and reactions.
Reductive activation of mitomycin C and mitomycin C metabolites catalyzed by NADPH-cytochrome P-450 reductase and xanthine oxidase
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