Ifosfamide-induced nephrotoxicity: mechanism and prevention.
The efficacy of ifosfamide (IFO), an antineoplastic drug, is severely limited by a high incidence of nephrotoxicity of unknown etiology. We hypothesized that inhibition of complex I (C-I) by chloroacetaldehyde (CAA), a metabolite of IFO, is the chief cause of nephrotoxicity, and that agmatine (AGM), which we found to augment mitochondrial oxidative phosphorylation and beta-oxidation, would prevent nephrotoxicity. Our model system was isolated mitochondria obtained from the kidney cortex of rats treated with IFO or IFO + AGM. Oxidative phosphorylation was determined with electron donors specific to complexes I, II, III, or IV (C-I, C-II, C-III, or C-IV, respectively). A parallel study was done with (13)C-labeled pyruvate to assess metabolic dysfunction. Ifosfamide treatment significantly inhibited oxidative phosphorylation with only C-I substrates. Inhibition of C-I was associated with a significant elevation of [NADH], depletion of [NAD], and decreased flux through pyruvate dehydrogenase and the TCA cycle. However, administration of AGM with IFO increased [cyclic AMP (cAMP)] and prevented IFO-induced inhibition of C-I. In vitro studies with various metabolites of IFO showed that only CAA inhibited C-I, even with supplementation with 2-mercaptoethane sulfonic acid. Following IFO treatment daily for 5 days with 50 mg/kg, the level of CAA in the renal cortex was approximately 15 micromol/L. Taken together, these observations support the hypothesis that CAA is accumulated in renal cortex and is responsible for nephrotoxicity. AGM may be protective by increasing tissue [cAMP], which phosphorylates NADH:oxidoreductase. The current findings may have an important implication for the prevention of IFO-induced nephrotoxicity and/or mitochondrial diseases secondary to defective C-I.
Nissim
Itzhak
I
Children's Hospital of Philadelphia, Division of Child Development, Rehabilitation Medicine and Metabolic Disease, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. ssitz@mail.med.upenn.edu
Horyn
Oksana
O
Daikhin
Yevgeny
Y
Nissim
Ilana
I
Luhovyy
Bohdan
B
Phillips
Peter C
PC
Yudkoff
Marc
M
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000376:Agmatine / Q000494:pharmacology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D004347:Drug Interactions; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors / Q000378:metabolism; D007069:Ifosfamide / Q000493:pharmacokinetics / Q000633:toxicity*; D007672:Kidney Cortex / Q000201:enzymology / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D008297:Male; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats
D018906:Antineoplastic Agents, Alkylating; D000376:Agmatine; C004656:chloroacetaldehyde; D042967:Electron Transport Complex I; D000079:Acetaldehyde; D007069:Ifosfamide