Inhibition of gene expression of organic cation/carnitine transporter and antioxidant enzymes in oxazaphosphorines-induced acute cardiomyopathic rat models.
It is well documented that high therapeutic doses of oxazaphosphorines, cyclophosphamide (CP) and ifosfamide (IFO), are associated with cardiomyopathy. This study investigated whether oxazaphosphorines alter the expression of organic cation/carnitine transporter (OCTN2) and antioxidant genes and if so, whether these alterations contribute to CP and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of six treatment groups namely, control, L carnitine, CP, IFO, CP plus L carnitine and IFO plus L carnitine. In cardiac and kidney tissues, CP and IFO significantly decreased mRNA and protein expression of OCTN2. Oxazaphosphorines significantly increased serum acyl-carnitine/free carnitine ratio and urinary carnitine excretion and significantly decreased total carnitine in cardiac tissues. Interestingly, carnitine supplementation completely reversed the biochemical and gene expression changes-induced by oxazaphosphorines to the control values, except OCTN2 expression remained inhibited by IFO. Data from this study suggest that: (1) Oxazaphosphorines decreased myocardial carnitine content following the inhibition of OCTN2 mRNA and protein expression in cardiac tissues. (2) Oxazaphosphorine therapy increased urinary loss of carnitine secondary to the inhibition of OCTN2 mRNA and protein expression in proximal tubules of the kidney. (3) Carnitine supplementation attenuates CP but not IFO-induced inhibition of OCTN2 mRNA and protein expression in heart and kidney tissues.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. sayedahmedmm@hotmail.com
Mohamed M
MM
Sayed-Ahmed
Meshan Lafi
ML
Aldelemy
Mohamed M
MM
Hafez
Othman A
OA
Al-Shabanah
D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D002331:Carnitine / Q000032:analysis / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood; D003520:Cyclophosphamide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007069:Ifosfamide / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D027701:Organic Cation Transport Proteins; D003520:Cyclophosphamide; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase; D002331:Carnitine; D007069:Ifosfamide