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A unique cytosolic activity related but distinct from NQO1 catalyses metabolic activation of mitomycin C

P Joseph1, A K Jaiswal

  • 1Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.

British Journal of Cancer
|February 7, 2001
PubMed

Insights

Dicoumarol inhibitable NAD(P)H:quinone oxidoreductase1 (NQO1) may play a minor role in Mitomycin C (MMC) activation. A distinct cytosolic activity, termed cytosolic MMC reductase, appears to be the primary catalyst for bioreductive activation of this anti-cancer drug.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Mitomycin C (MMC) is a bioreductive anticancer drug used for various cancers.
  • NAD(P)H:quinone oxidoreductase1 (NQO1) has been implicated in the bioreductive activation of MMC, leading to DNA cross-linking and cytotoxicity.
  • The precise role of NQO1 in MMC metabolic activation remains debated.

Purpose of the Study:

  • To investigate the role of NQO1 in the bioreductive activation of Mitomycin C (MMC).
  • To identify the specific enzyme(s) responsible for catalyzing MMC activation.
  • To differentiate the activity of NQO1 from other potential MMC-activating enzymes.

Main Methods:

  • Development of Chinese hamster ovary (CHO) cells with stably overexpressed NQO1.
  • Generation of NQO1 knockout (NQO1-/-) mice using homologous recombination.
  • Analysis of MMC-induced DNA cross-linking and cytotoxicity in NQO1-overexpressing cells and NQO1-/- mice.
  • Characterization of cytosolic enzyme activity in liver and colon tissues.

Main Results:

  • NQO1-overexpressing CHO cells showed increased protection against menadione but no altered sensitivity to MMC.
  • NQO1-/- mice exhibited similar levels of MMC-induced DNA cross-linking in liver and colon cytosolic fractions compared to wild-type mice.
  • A unique dicoumarol-inhibitable and immunologically related cytosolic activity, designated cytosolic MMC reductase, was identified as responsible for MMC activation in NQO1-deficient tissues.

Conclusions:

  • NQO1 plays a minimal role in the bioreductive activation of Mitomycin C.
  • A distinct cytosolic enzyme, cytosolic MMC reductase, is the primary catalyst for MMC activation.
  • These findings clarify the metabolic activation pathway of MMC, potentially impacting its therapeutic application.

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