title: Adriamycin-induced hepatic and myocardial lipid peroxidation and DNA damage, and enhanced excretion of urinary lipid metabolites in rats.
abstract: Adriamycin produces clinically useful responses in a variety of human cancers including lymphomas, leukemias, and solid tumors. However, the toxicity of adriamycin has limited its usefulness. Iron-catalyzed free radical reactions as the peroxidation of membrane lipids, inactivation of critical enzymes, and the inhibition of DNA, RNA and protein synthesis in heart, liver and kidney have been implicated in the toxicity of adriamycin. In order to further assess the role of oxidative stress in the toxicity of adriamycin, the effects of adriamycin were examined on the urinary excretion of lipid metabolites at 0, 6, 12, 24, 48 and 72 h post-treatment, and on myocardial and hepatic lipid peroxidation and nuclear DNA single strand breaks at 24 h post-treatment following single oral and intravenous (i.v.) doses of 10 mg/kg adriamycin. Urinary malondialdehyde (MDA), formaldehyde (FA), acetaldehyde (ACT) and acetone (ACON) excretion was significantly increased at all time points examined. Following the oral administration of adriamycin, maximum excretion of MDA, FA, ACT and ACON of 6.2-, 2.7-, 3.7- and 2.2-fold relative to control values, respectively, occurred 24 h after treatment. However, following the i.v. administration of adriamycin, greatest increases in excretion of MDA, FA and ACT reaching 6.9-, 3.3- and 6.3-fold relative to control values, respectively, were observed 6 h after treatment, while the greatest increase in ACON excretion of 4.2-fold relative to control values occurred 12 h post-treatment. Following oral and i.v. administration of adriamycin, significant increases were observed in myocardial and hepatic lipid peroxidation in mitochondrial and microsomal membranes, and myocardial and hepatic nuclei DNA single strand breaks 24 h after treatment. The results indicate that adriamycin administration induces myocardial and hepatic lipid peroxidation which may be responsible for enhanced excretion of urinary lipid metabolites as a result of membrane damage, and also induces enhanced DNA damage. These effects may be due to adriamycin-induced production of reactive oxygen species.
authors: Department of Pharmaceutical Sciences, Creighton University Health Sciences Center, Omaha, NE 68178.
authors: D
authors: D
authors: Bagchi
authors: M
authors: M
authors: Bagchi
authors: E A
authors: EA
authors: Hassoun
authors: J
authors: J
authors: Kelly
authors: S J
authors: SJ
authors: Stohs
mesh_terms: D000079:Acetaldehyde / Q000652:urine; D000096:Acetone / Q000652:urine; D000284:Administration, Oral; D000447:Aldehydes / Q000652:urine*; D000818:Animals; D004249:DNA Damage; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D005557:Formaldehyde / Q000652:urine; D007275:Injections, Intravenous; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008315:Malondialdehyde / Q000652:urine; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000447:Aldehydes; D000096:Acetone; D005557:Formaldehyde; D008315:Malondialdehyde; D004317:Doxorubicin; D000079:Acetaldehyde