Reversal of doxorubicin-induced cardiac metabolic damage by L-carnitine.
Biopharmacological evaluations of the protective effects of L-carnitine (a naturally occurring quaternary ammonium compound) against doxorubicin-induced metabolic damage were carried out in isolated cardiac myocytes and in isolated rat heart mitochondria. Perfusion of the heart with DOX (0.5 mM) caused a significant 70% inhibition of palmitate oxidation in cardiac myocytes, while L-carnitine (5 mM) perfusion caused stimulation which accounted for 37%. Perfusion of the heart with L-carnitine after 10-min perfusion with DOX (0.5 mM) caused 88% reversal of DOX-induced inhibition of palmitate oxidation in cardiac cells. In rat heart mitochondria, DOX has no effect on either palmitate oxidation or acyl-CoA synthetase activity, whereas Enoximone (c-AMP-dependent phosphodiesterase inhibitor), caused a significant inhibition of palmitate oxidation and acyl-CoA activity (40 and 27%, respectively). The oxidation of palmitoyl-CoA, an index of carnitine palmitoyltransferse reaction was significantly inhibited by DOX as a function of DOX concentration. Preincubation of mitochondria with L-carnitine caused reversal of DOX-induced inhibition of palmitoyl-CoA oxidation depending on the concentration of L-carnitine. Moreover, L-carnitine treatment did not interfere with the cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. The findings of this study may suggest that inhibition of fatty acid oxidation in the heart is at least a part of doxorubicin cardiotoxicity and that L-carnitine can be used to prevent the doxorubcin-induced cardiac metabolic damage without interfering with its antitumour activities.
Sayed-Ahmed
M M
MM
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
Shaarawy
S
S
Shouman
S A
SA
Osman
A M
AM
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000473:pathology; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D002331:Carnitine / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D019308:Palmitic Acid; D004317:Doxorubicin; D002331:Carnitine