title: Absence of acute doxorubicin-induced dysfunction of heart mitochondrial oxidative phosphorylation and creatine kinase activities.
abstract: Since reductions in cardiac high-energy phosphate content and dysfunction of mitochondrial activities have been demonstrated after doxorubicin exposure, one mechanism of doxorubicin cardiotoxicity has been thought to be an interference with mitochondrial energy metabolism. To determine whether mitochondrial dysfunction is induced by acute drug exposure, isolated rat hearts were perfused with 10(-5) M doxorubicin for 70 min followed by mitochondrial isolation. Rates of electron transport, creatine kinase activity, acceptor control, respiratory control, and ADP/O ratios were assayed and correlated to doxorubicin-induced abnormalities in left ventricular function. At doses of doxorubicin sufficient to cause a marked deterioration of left ventricular systolic pressure and a rise in end-diastolic pressure, no decreases were noted in the measured mitochondrial parameters with either glutamate plus malate or succinate as respiratory substrates. In fact, in some cases the rates of electron transport were higher in mitochondria isolated from the treated hearts. In addition, isolated heart mitochondria were directly incubated in doxorubicin at doses as high as 10(-4) M for up to 70 min at 0 and 20 degrees C and 1.5 min at 37 degrees C. Under these conditions functional impairment of mitochondrial respiration was also not detected. Therefore, it appears that acute doxorubicin cardiotoxicity cannot be related to primary mitochondrial defects in high-energy phosphate metabolism. These data lend further support to the notion that doxorubicin cardiotoxicity may be fundamentally related to changes in coronary vascular resistance and resultant damage induced by hypoperfusion.
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D008293:Malates / Q000378:metabolism; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D010766:Phosphorylation; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D005971:Glutamates; D008293:Malates; D018698:Glutamic Acid; D004317:Doxorubicin; C030298:malic acid; D003402:Creatine Kinase