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Ifosfamide‐induced nephrotoxicity : Mechanism and prevention
Author(s) -
Nissim Itzhak,
Horyn Oksana,
Nissim Ilana,
Daikhin Yevgeny,
Luhovyy Bohdan,
Yudkoff Marc
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a893
Subject(s) - nephrotoxicity , glutamine , chemistry , metabolite , mitochondrion , respiratory chain , biochemistry , renal cortex , pharmacology , ifosfamide , kidney , endocrinology , biology , medicine , cisplatin , chemotherapy , amino acid
Ifosfamide (IFO) is an anti‐tumor prodrug effective against many solid tumors. Therapeutic efficacy is limited by a high incidence of renal damage. We examined the effect of IFO on renal mitochondrial function. We hypothesized that IFO metabolites inhibit NADH:ubiquinone oxidoreductase (complex I; C‐I), which is sensitive to free radicals, thereby impairing the respiratory chain (RC) and oxidative phosphorylation (OP). We further hypothesized that provision of substrate to complex‐II (C‐II) would prevent IFO‐induced injury by bypassing C‐I. We tested RC activity in renal cortical mitochondria from rats treated with IFO, IFO+agmatine (a stimulator of fatty acid oxidation) or IFO+glutamine. Mitochondria of IFO‐treated rats show a 50% decrease in State 3 respiration with C‐I substrates but not with C‐II substrates. Inhibition of C‐I significantly increased [NADH] and decreased [NAD] in kidney cortex of these rats. The in vivo supplementation with agamatine or glutamine reversed inhibition of the RC and OP. Agmatine may furnish more FADH2 to C‐II. Glutamine may supply succinate to C‐II after conversion to glutamate and 2‐oxo‐glutarate. In in vitro studies we found that chloroacetaldehyde (CAA), a IFO metabolite, inhibited C‐I and OP by 60% without affecting C‐II. Disruption of C‐I by CAA probably is the primary lesion of IFO‐induced nephrotoxicity. Supplementation with C‐II substrates ameliorates ‐ and even might prevent ‐ renal damage. Supported by NIH, DK‐53761 and CA‐79495 (to I.N.)