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Bis(alkylamino)anthracenedione antineoplastic agent metabolic activation by NADPH-cytochrome P-450 reductase and NADH dehydrogenase: diminished activity relative to anthracyclines.

Publication ,  Journal Article
Kharasch, ED; Novak, RF
Published in: Arch Biochem Biophys
July 15, 1983

Stimulation of the rates of NAD(P)H oxidation, superoxide generation, and hydrogen peroxide formation by three anthracenedione antineoplastic agents in the presence of NADPH-cytochrome P-450 reductase, NADH dehydrogenase, or rabbit hepatic microsomes was studied and the results compared with those obtained for the anthracyclines Adriamycin and daunorubicin. In all cases the anthracenediones, including mitoxantrone and ametantrone, were significantly (5- to 20-fold) less effective than the anthracyclines in stimulating NAD(P)H oxidation, superoxide formation, or hydrogen peroxide production. Of the three anthracenediones studied, the ring-monohydroxylated compound showed the greatest activity followed by the ring-dihydroxylated derivative (mitoxantrone). In contrast, the non-ring-hydroxylated anthracenedione (ametantrone) was a relatively ineffective electron acceptor and inhibited the reduction of more effective acceptors such as Adriamycin. Michaelis-Menten kinetic constants were determined by analysis of the rates of NADPH oxidation. NADP+ and 2'-AMP inhibited the reduction of the ring-hydroxylated anthracenediones and anthracyclines, demonstrating the enzymatic nature of the reaction. The non-ring-hydroxylated anthracenedione inhibited the reduction of Adriamycin by both P-450 reductase and NADH dehydrogenase with 50% inhibition achieved at approximately 300 microM. Thus, there appears to exist a structural relationship between anthracenedione ring hydroxylation and metabolic activation. These results also suggest that the relative inability of the anthracenediones to function as artificial electron acceptors in comparison to the anthracyclines may be correlated with diminished anthracenedione cardiotoxicity.

Duke Scholars

Published In

Arch Biochem Biophys

DOI

ISSN

0003-9861

Publication Date

July 15, 1983

Volume

224

Issue

2

Start / End Page

682 / 694

Location

United States

Related Subject Headings

  • Rabbits
  • Quinones
  • Oxidation-Reduction
  • Naphthacenes
  • NADPH-Ferrihemoprotein Reductase
  • NADH Dehydrogenase
  • Microsomes, Liver
  • Male
  • In Vitro Techniques
  • Hydrogen Peroxide
 

Citation

Journal cover image

Published In

Arch Biochem Biophys

DOI

ISSN

0003-9861

Publication Date

July 15, 1983

Volume

224

Issue

2

Start / End Page

682 / 694

Location

United States

Related Subject Headings

  • Rabbits
  • Quinones
  • Oxidation-Reduction
  • Naphthacenes
  • NADPH-Ferrihemoprotein Reductase
  • NADH Dehydrogenase
  • Microsomes, Liver
  • Male
  • In Vitro Techniques
  • Hydrogen Peroxide