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Please use this identifier to cite or link to this item: http://hdl.handle.net/123456789/18582

Title: Carnitine deficiency and oxidative stress provoke cardiotoxicity in an ifosfamide-induced Fanconi Syndrome rat model
Authors: M, Mohamed.
Ahmed, Sayed.
Q. Darweesh, Amal.
J. Fatani, Amal.
Keywords: ifosfamide, Fanconi Syndrome, carnitine deficiency, cardiotoxicity, D-carnitine, mildronate, propionyl-L-carnitine
Issue Date: 2010
Publisher: Oxidative Medicine and Cellular Longevity
Citation: Oxidative Medicine and Cellular Longevity 3:4, 266-274
Abstract: In addition to hemorrhagic cystitis, Fanconi Syndrome is a serious clinical side effect during ifosfamide (IFO) therapy. Fanconi syndrome is a generalized dysfunction of the proximal tubule which is characterized by excessive urinary excretion of glucose, phosphate, bicarbonate, amino acids and other solutes excreted by this segment of the nephron including L-carnitine. Carnitine is essential cofactor for β-oxidation of long-chain fatty acids in the myocardium. IFO therapy is associated with increased urinary carnitine excretion with subsequent secondary deficiency of the molecule. Cardiac abnormalities in IFO-treated cancer patients were reported as isolated clinical cases. This study examined whether carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, provoke IFO-induced cardiomyopathy as well as exploring if carnitine supplementation using Propionyl-L-carnitine (PLC) could offer protection against this toxicity. In the current study, an animal model of carnitine deficiency was developed in rats by D-carnitine-mildronate treatment Adult male Wistar albino rats were assigned to one of six treatment groups: the first three groups were injected intraperitoneally with normal saline, D-carnitine (DC, 250 mg/kg/day) combined with mildronate (MD, 200 mg/kg/day) and PLC (250 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups were injected with the same doses of normal saline, DC-MD and PLC, respectively for 5 successive days before and 5 days concomitant with IFO (50 mg/kg/day). IFO significantly increased serum creatinine, blood urea nitrogen (BUN), urinary carnitine excretion and clearance, creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), intramitochondrial acetyl-CoA/CoA-SH and thiobarbituric acid reactive substances (TBARS) in cardiac tissues and significantly decreased adenosine triphosphate (ATP) and total carnitine and reduced glutathione (GSH ) content in cardiac tissues. In carnitine-depleted rats, IFO induced dramatic increase in serum creatinine, BUN, CK-MB, LDH, carnitine clearance and intramitochondrial acetyl-CoA/CoA-SH , as well as progressive reduction in total carnitine and ATP in cardiac tissues. Interestingly, PLC supplementation completely reversed the biochemical changes-induced by IFO to the control values. In conclusion, data from the present study suggest that: Carnitine deficiency and oxidative stress, secondary to Fanconi Syndrome, constitute risk factors and should be viewed as mechanisms during development of IFO-induced cardiotoxicity. Carnitine supplementation, using PLC, prevents the development of IFO-induced cardiotoxicity through antioxidant signalling and improving mitochondrial function.
URI: http://hdl.handle.net/123456789/18582
ISSN: 1942-0900
Appears in Collections:College of Applied Medical Sciences

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