Myocardial damage induced by doxorubicins: hydroperoxide-initiated chemiluminescence and morphology.
Doxorubicin (1.2 mg/kg body weight) or 4'-epidoxorubicin (1.7 mg/kg body weight) was injected intravenously to rabbits twice a week during 7 to 8 weeks. Total doses were 17.9 +/- 0.2 mg and 24.4 +/- 0.3 mg, respectively. Heart, liver, muscle, and brain homogenates from treated and control animals were supplemented with 3 mM tert-butyl hydroperoxide and hydroperoxide-initiated chemiluminescence was measured. Heart homogenates from doxorubicin-treated rabbits showed an increased hydroperoxide-initiated chemiluminescence (77.2 +/- 3.9; expressed as cpm/mg protein X 10(-3]; whereas 4'-epidoxorubicin-treated rabbits did not exhibit changes (40.7 +/- 4.6) when both were compared with the untreated animals (41.3 +/- 3.0). Liver, muscle, and brain homogenates from doxorubicin and 4'-epidoxorubicin-treated animals showed a hydroperoxide-initiated chemiluminescence that was similar to the one from control animals. Microscopically, the total extent of the myocardial damage (as percentage of damaged myocytes) was markedly higher in the doxorubicin-treated rabbits (63.0 +/- 8.6) than in the 4'-epidoxorubicin-treated group (34.6 +/- 5.0); being both values higher than the one corresponding to control animals (8.0 +/- 1.1). The subendocardial areas of the septum and of the left ventricle were highly sensitive to doxorubicin damage. Hydroperoxide-initiated chemiluminescence of whole heart homogenate correlated statistically with the microscopic tissue damage in the subendocardial and intramural areas of the right ventricle. It is concluded that chronic administration of doxorubicins lead to oxidative stress of the myocardium and that 4'-epidoxorubicin produces less severe oxidative stress and less extensive myocardial damage than those provoked by lower doses of doxorubicin.
Llesuy
S F
SF
Institute of Biochemistry and Biophysics, School of Pharmacy and Biochemistry, University of Buenos Aires, Argentina.
Milei
J
J
Gonzalez Flecha
B S
BS
Boveris
A
A
D000818:Animals; D004317:Doxorubicin / Q000633:toxicity*; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D005609:Free Radicals; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008163:Luminescent Measurements; D008297:Male; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011817:Rabbits
D005609:Free Radicals; D015251:Epirubicin; D004317:Doxorubicin; D006861:Hydrogen Peroxide