Propionyl-L-carnitine as potential protective agent against adriamycin-induced impairment of fatty acid beta-oxidation in isolated heart mitochondria.
Propionyl-L-carnitine (PLC), a natural short-chain derivative of L-carnitine, has been tested in this study as a potential protective agent against adriamycin (ADR)-induced cardiotoxicity in isolated rat heart myocytes and mitochondria. In cardiac myocytes, ADR (0.5 mM) caused a significant (70%) inhibition of palmitate oxidation, whereas, PLC (5 mM) induced a significant (49%) stimulation. Addition of PLC to ADR-incubated myocytes induced 79% reversal of ADR-induced inhibition of palmitate oxidation. In isolated rat heart mitochondria, ADR produced concentration-dependent inhibition of both palmitoyl-CoA and palmitoyl-carnitine oxidation, while PLC caused a more than 2.5-fold increase in both substrates. Preincubation of mitochondria with 5 mM PLC caused complete reversal of ADR-induced inhibition in the oxidation of both substrates. Also ADR induced concentration-dependent inhibition of CPT I which is parallel to the inhibition of its substrate palmitoyl-CoA. In rat heart slices, ADR induced a significant (65%) decrease in adenosine triphosphate (ATP) and this effect is reduced to 17% only by PLC. Results of this study revealed that ADR induced its cardiotoxicity by inhibition of CPT I and beta-oxidation of long-chain fatty acids with the consequent depletion of ATP in cardiac tissues, and that PLC can be used as a protective agent against ADR-induced cardiotoxicity.
Sayed-Ahmed
M M
MM
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Fum El-Khalig, Kasr El-Aini Street, Cairo, Egypt.
Shouman
S A
SA
Rezk
B M
BM
Khalifa
M H
MH
Osman
A M
AM
El-Merzabani
M M
MM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D002316:Cardiotonic Agents / Q000378:metabolism / Q000494:pharmacology*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D005227:Fatty Acids; D010168:Palmitates; D011506:Proteins; C003223:propionylcarnitine; D010171:Palmitoyl Coenzyme A; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine