Increased iron content in rat myocardium after 5-fluorouracil chronic administration.
The isovolumic perfused rat heart model according to Langendorff has been used in order to characterize the changes occurring in the heart following 5-Fluorouracil (5-FU) administration. Preliminary published data pointed out that perfusion of isolated heart with 1 mg/l 5-FU failed to show any differences in contractility and oxygen consumption in comparison with the control group. However, when Wistar rats received 5-FU once a day (50 mg/kg, I.P.) for five consecutive days a consistent increase in oxygen consumption throughout the 80 min of perfusion associated with a decrease in the fractional extraction of oxygen and a lowered + dP/dt max were observed, without any drug added during the in vitro perfusion. Further investigation has been performed for a better understanding of the results observed after 5-FU pretreatment. Magnesium, potassium, calcium, copper and iron contents in the myocardium (at 0 min of perfusion) were measured by flame atomic absorption spectrophotometry. Iron levels were 20% higher in the 5-FU pretreated group than in the control group, whereas as no differences were observed for the other elemental concentrations. Both initial glycogen and ATP contents were respectively 42% and 29% higher in the pretreated than in the control group and alpha-hydroxybutyrate dehydrogenase release was lower after 40 min of perfusion in the pretreated group. However, 5-FU pretreatment increased net tissue water gain after 80 min of perfusion. Increases in mean oxygen partial pressure in the myocardium and in oxygen consumption associated with increased iron level might be candidates responsible for 5-FU induced cardiotoxicity through an increased in oxygen derived free radicals. Sympathetic over-stimulation or calcium overload do not appear to be involved in 5-FU induced cardiotoxicity.
Millart
H
H
Laboratoire de Pharmacologie Médicale, Faculté de Médecine, Reims, France.
Kantelip
J P
JP
Platonoff
N
N
Descous
I
I
Trenque
T
T
Lamiable
D
D
Choisy
H
H
D000818:Animals; D005472:Fluorouracil / Q000009:adverse effects*; D006321:Heart / Q000187:drug effects*; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism; D007501:Iron / Q000032:analysis*; D008297:Male; D009206:Myocardium / Q000737:chemistry* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D007501:Iron; C035749:2-hydroxybutyrate dehydrogenase; D006884:Hydroxybutyrate Dehydrogenase; D005472:Fluorouracil