Progression of cyclophosphamide-induced acute renal metabolic damage in carnitine-depleted rat model.

BACKGROUND: Little information is available regarding the mechanism of cyclophosphamide (CP)-induced renal damage. Therefore, this study examined whether carnitine deficiency constitutes a risk factor in and should be viewed as a mechanism during development of CP-induced nephrotoxicity and explored whether carnitine supplementation, using propionyl-L-carnitine (PLC), could offer protection against this toxicity. METHODS: Experimental rats were assigned to one of six groups; the first three groups were injected intraperitoneally with normal saline, PLC (250 mg/kg/day) or D-carnitine (250 mg/kg/day) + Mildronate (200 mg/kg/day), respectively, for 10 successive days. The 4th, 5th and 6th groups received the same doses of normal saline, PLC or D-carnitine + Mildronate, respectively, for 5 successive days before and after a single dose of CP (200 mg/kg). RESULTS: CP significantly increased serum creatinine, blood urea nitrogen (BUN), intramitochondrial acetyl-coenzyme A (CoA) and thiobarbituric acid reactive substances, significantly decreased total carnitine, intramitochondrial CoA-SH, adenosine triphosphate (ATP) and ATP/adenosine diphosphate (ADP) and reduced glutathione in kidney tissues. In carnitine-depleted rats, CP resulted in dramatic increase in serum nephrotoxicity indices and acetyl-CoA and induced progressive reduction in total carnitine, CoA-SH and ATP as well as severe histopathological lesions in kidney tissues. Interestingly, PLC completely reversed the biochemical and histopathological changes induced by CP to normal values. CONCLUSIONS: Oxidative stress is not involved in CP-induced renal injury in this model. Carnitine deficiency and energy starvation constitute risk factors in and should be viewed as a mechanism during CP-induced nephrotoxicity. PLC prevents development of CP-induced nephrotoxicity by increasing intracellular carnitine content, intramitochondrial CoA-SH/acetyl-CoA ratio and energy production.