title: Doxorubicin-induced acute changes in cytotoxic aldehydes, antioxidant status and cardiac function in the rat.
abstract: Doxorubicin (DOX)-induced cardiotoxicity is thought to be caused by free radical-mediated mechanisms. An in vivo rat model was developed to investigate the DOX-induced cascade of early biochemical changes focusing on the central role of the aldehydic lipid peroxidation products. Antioxidant status was evaluated by glutathione measurements. Creatine Kinase (CK) activity was measured as an index of cardiac injury. Development of functional abnormalities were documented by echocardiography. The results showed that aldehydes in rat plasma and heart tissues increased significantly following DOX treatment. The changes occurred early, peaked around 2 h after DOX administration, and the levels declined or returned to baseline value within 8-24 h. Toxic aldehyde levels including malondialdehyde, hexanal and 4-hydroxy-non-2-enal also increased. Acyloin levels, metabolic products of aldehydes, increased early and then decreased in plasma, and there was a significant decrease in heart tissues after DOX treatment. GSH levels decreased early, then increased by 24 h, while GSSG levels decreased initially, then increased after DOX treatment, suggesting early depletion of GSH and a later rebound phenomenon. CK levels were elevated after treatment. The functional abnormalities were documented by stress echocardiography in some rats although the changes were not consistent at such an early stage following treatment. Our data confirmed the involvement of free radicals, and suggested that the cytotoxic aldehydes play a central role in initiating the steps that lead to functional impairment of the myocardium following DOX administration. Scavengers and the metabolic removal of some of the aldehydes also play a role in protecting the myocardium against injury.
authors.affiliation: Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: Y
authors.initials: Y
authors.lastname: Evrovsky
authors.forename: D
authors.initials: D
authors.lastname: Cole
authors.forename: J
authors.initials: J
authors.lastname: Trines
authors.forename: L N
authors.initials: LN
authors.lastname: Benson
authors.forename: D C
authors.initials: DC
authors.lastname: Lehotay
mesh_terms: D000447:Aldehydes / Q000097:blood / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D009202:Cardiomyopathies / Q000209:etiology; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D004452:Echocardiography; D005609:Free Radicals / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives / Q000097:blood; D019803:Glutathione Disulfide; D006321:Heart / Q000187:drug effects; D007659:Ketones / Q000097:blood / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D005609:Free Radicals; D007659:Ketones; D004317:Doxorubicin; D003402:Creatine Kinase; D005978:Glutathione; D019803:Glutathione Disulfide