Downregulation of Oxidative and Nitrosative Apoptotic Signaling by L-Carnitine in Ifosfamide-Induced Fanconi Syndrome Rat Model

Abstract

It is well documented that ifosfamide (IFO) therapy is associated with sever nephropathy in the form of Fanconi syndrome. Although oxidative stress has been reported as a major player in IFO-induced Fanconi syndrome, no mechanism for this effect has been ascertained. Therefore, this study has been initiated to investigate, on gene expression level, the mechanism of IFO-induce nephrotoxicity and those whereby carnitine supplementation attenuates this serious side effect of IFO. To achieve the ultimate goals of this study, adult male rats were assigned to one of four treatment groups, namely, control, L-carnitine, IFO, and IFO plus L-carnitine. Administration of IFO for 5 days significantly increased serum creatinine, blood urea nitrogen (BUN), and total nitrate/nitrite (NOx) production in kidney tissues. In addition, IFO significantly increased mRNA expression of inducible nitric oxide synthase (iNOS), caspase-9, and caspase-3 and significantly decreased expression of glutathione peroxides (GPx), catalase (CAT), and Bcl2 in kidney tissues. Administration of L-carnitine to IFO-treated rats resulted in a complete reversal of the all biochemical and gene expression changes, induced by IFO, to the control values. Data from this study suggest that L-carnitine prevents the development of IFO-induced nephrotoxicity via downregulation of oxidative and nitrosative apoptotic signaling in kidney tissues.

Fundamental role of warburg effect in various pathophysiological processes

“…In pathological states of the renal system, it may go to the extreme irreversible dedifferentiation states.Urine lactate has been shown to be increased in Fanconi's syndrome (168). Increased NO due to iNOS activation has been shown in animal model Fanconi's syndrome (169). It has been already shown that in response to injury to renal system, the surviving cells dedifferentiate and repair the injury (161).…”

PharmGKB summary

“…Other mechanisms by IPM that reduce cancer proliferation, including activation of proapoptotic pathways and reduction of inflammatory and antiapoptotic pathways, have also been suggested [12, 13] (Fig. 2).…”

“…Both CYP3A and CYP2B6 catalyze this reaction, but striking differences are observed: CYP3A4/5 preferentially produced (R)- N -2-DCl-IFO and (R)- N -3-DCl-IFO from R-IFO and S-IFO, respectively, whereas CYP2B6 preferentially formed (S)- N -3-DCl-IFO and (S)- N -2-DCl-IFO. On the basis of these in-vitro data, R-IFO exhibits more rapid 4-hydroxylation and less efficient N -dechloroethylation to toxic metabolites than S-IFO, suggesting that R-IFO may have a distinct clinical advantage over racemic IFO [12]. Although in-vivo studies on the metabolism and disposition of the R-enantiomer and S-enantiomer of IFO have not been fully evaluated, the limited clinical data available are consistent with the in-vitro evidence.…”

“…IFO increases the gene expression levels of caspases 3 and 9, whereas it decreases the expression of BCL2 , a caspase inhibitor. Not only does IFO decrease the possibility of BCL2 blocking the release of cytochrome c from the mitochondria but IFO can activate BAX and BAK , which are procytochrome c releasers [12, 14]. …”

Fatigue and carnitine levels over multiple cycles of chemotherapy in children and adolescents

“…Carnitine binds to the chloroacetyl-CoA, detoxifies it, and the chloro-acteyl-carnitine is excreted in the urine. This detoxification results in a secondary deficiency of carnitine in patients receiving ifosfamide (Peluso et al, 2000;Sayed-Ahmed et al, 2012). Cisplatin can damage the kidney resulting in a reduction in glomerular filtration and tubular damage.…”