Inhibition of gene expression of carnitine palmitoyltransferase I and heart fatty acid binding protein in cyclophosphamide and ifosfamide-induced acute cardiotoxic rat models.
This study investigated whether cyclophosphamide (CP) and ifosfamide (IFO) therapy alters the expression of the key genes engaged in long-chain fatty acid (LCFA) oxidation outside rat heart mitochondria, and if so, whether these alterations should be viewed as a mechanism during CP- and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of the six treatment groups: Rats in group 1 (control) and group 2 (L-carnitine) were injected intraperitoneal (i.p.) with normal saline and L-carnitine (200 mg/kg/day), respectively, for 10 successive days. Animals in group 3 (CP group) were injected i.p. with normal saline for 5 days before and 5 days after a single dose of CP (200 mg/kg, i.p.). Rats in group 4 (IFO group) received normal saline for 5 successive days followed by IFO (50 mg/kg/day, i.p.) for 5 successive days. Rats in group 5 (CP-carnitine supplemented) were given the same doses of L-carnitine as group 2 for 5 days before and 5 days after a single dose of CP as group 3. Rats in group 6 (IFO-carnitine supplemented) were given the same doses of L-carnitine as group 2 for 5 days before and 5 days concomitant with IFO as group 4. Immediately, after the last dose of the treatment protocol, blood samples were withdrawn and animals were killed for biochemical, histopathological and gene expression studies. Treatment with CP and IFO significantly decreased expression of heart fatty acid binding protein (H-FABP) and carnitine palmitoyltransferase I (CPT I) genes in cardiac tissues. Moreover, CP but not IFO significantly increased acetyl-CoA carboxylase2 mRNA expression. Conversely, IFO but not CP significantly decreased mRNA expression of malonyl-CoA decarboxylase. Both CP and IFO significantly increased serum lactate dehydrogenase, creatine kinase isoenzyme MB and malonyl-CoA content and histopathological lesions in cardiac tissues. Interestingly, carnitine supplementation completely reversed all the biochemical, histopathological and gene expression changes induced by CP and IFO to the control values, except CPT I mRNA, and protein expression remained inhibited by IFO. Data from the current study suggest, for the first time, that (1) CP and IFO therapy is associated with the inhibition of the expression of H-FABP and CPT I genes in cardiac tissues with the consequent inhibition of mitochondrial transport and oxidation of LCFA. (2) The progressive increase in cardiotoxicity enzymatic indices and the decrease in H-FABP and CPT I expression may point to the possible contribution of these genes to CP- and IFO-induced cardiotoxicity.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451, Kingdom of Saudi Arabia, sayedahmedmm@hotmail.com.
Mohamed M
MM
Sayed-Ahmed
Meshan L
ML
Aldelemy
Othman A
OA
Al-Shabanah
Mohamed M
MM
Hafez
Khaled A
KA
Al-Hosaini
Naif O
NO
Al-Harbi
Shakir D
SD
Al-Sharary
Mohamed M
MM
Al-Harbi
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D066126:Cardiotoxicity / Q000473:pathology; D002331:Carnitine / Q000627:therapeutic use; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics*; D052279:Creatine Kinase, MB Form / Q000097:blood; D003520:Cyclophosphamide / Q000633:toxicity*; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007069:Ifosfamide / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
D018906:Antineoplastic Agents, Alkylating; D050556:Fatty Acid-Binding Proteins; D012333:RNA, Messenger; D008316:Malonyl Coenzyme A; D003520:Cyclophosphamide; D007770:L-Lactate Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase; D052279:Creatine Kinase, MB Form; D002331:Carnitine; D007069:Ifosfamide