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Biochemical determinants of Adriamycin toxicity in mouse liver, heart and intestine

A L Odom1, C A Hatwig, J S Stanley

  • 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205-7199.

Biochemical Pharmacology
|February 18, 1992
PubMed

Insights

Adriamycin toxicity varies by organ due to biochemical differences. The liver

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Adriamycin (doxorubicin) is a potent chemotherapy agent with known organ toxicities.
  • Differential susceptibility of liver, heart, and intestine to Adriamycin toxicity is not fully understood.
  • Understanding these biochemical differences is crucial for managing Adriamycin-induced side effects.

Purpose of the Study:

  • To investigate the biochemical characteristics underlying the differential susceptibility of mouse liver, heart, and intestine to acute Adriamycin toxicity.
  • To elucidate the mechanisms of Adriamycin-induced oxidative stress and thiol depletion in these organs.

Main Methods:

  • Female CD-1 mice were administered intravenous Adriamycin at doses ranging from 23-30 mg/kg.
  • Biochemical parameters including glutathione, glutathione peroxidase, non-protein thiols, lipid peroxides, and DT-diaphorase activity were measured in liver, heart, and intestine.
  • Adriamycin and its metabolites' covalent binding to tissue macromolecules was assessed.

Main Results:

  • The liver, relatively resistant to Adriamycin, showed high glutathione and glutathione peroxidase levels, with transient non-protein thiol depletion and no lipid peroxidation, suggesting effective antioxidant defense.
  • Adriamycin induced significant lipid peroxidation in the heart, indicating oxidative damage, but no decrease in non-protein thiols.
  • Heart and intestine exhibited low glutathione peroxidase activity, potentially limiting antioxidant capacity, while DT-diaphorase activity was high and induced in the liver.

Conclusions:

  • Differential Adriamycin toxicity is linked to organ-specific variations in antioxidant enzyme activity (glutathione peroxidase, DT-diaphorase) and thiol levels.
  • The liver's resistance is attributed to robust antioxidant defenses, while cardiac oxidative damage may exacerbate cardiotoxicity.
  • DT-diaphorase may play a role in Adriamycin metabolism, influencing organ-specific toxicity.

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