Ifosfamide induces acute renal failure via inhibition of the thioredoxin reductase activity.
The present study investigated the impact of ifosfamide (IFO) on renal thioredoxin reductase (TrxR) activity. In mice treated with IFO for 6 h, TrxR activity significantly decreased in a dose-dependent manner. Subsequently, acute renal failure (ARF) occurred dose-dependently. Like IFO, the well-established TrxR-specific inhibitor auranofin suppresfssed renal TrxR activity and generated ARF too. TrxR was inactivated by IFO preferentially over other antioxidant parameters at 6 h; however, it recovered nearly to normal levels within 12 h. When auranofin was administered at 6 h after IFO treatment, the recovery at 12 h was sharply attenuated. Consequently, ARF was pronouncedly exacerbated. IFO within its maximum tolerated dose did not considerably deplete renal glutathione. However, escalating IFO dose strikingly attacked both the thioredoxin and the glutathione systems, resulting in lethality, which implies that glutathione depletion sensitizes IFO-induced nephrotoxicity and cosuppression of both systems causes more severe toxicological consequences than suppressing the thioredoxin system alone. Indeed, combining IFO with buthionine sulfoximine, an inhibitor of glutathione synthesis, induced much more severe ARF than IFO alone did. Taken together, inhibition of renal TrxR activity can be considered as a pivotal mechanism of IFO-induced ARF, and individuals with lower levels of renal glutathione are at high risk of incurring ARF after IFO treatment.
School of Chemistry and Material Science, University of Science and Technology of China, Hefei 230052, Anhui, People's Republic of China. zjszyzzc@mail.hf.ah.cn
Jinsong
J
Zhang
Hongjuan
H
Lu
D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000201:enzymology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000633:toxicity; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001310:Auranofin / Q000008:administration & dosage / Q000633:toxicity; D019328:Buthionine Sulfoximine / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007069:Ifosfamide / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*
D018906:Antineoplastic Agents, Alkylating; D000975:Antioxidants; D004791:Enzyme Inhibitors; D005609:Free Radicals; D001310:Auranofin; D019328:Buthionine Sulfoximine; D013880:Thioredoxin-Disulfide Reductase; D005978:Glutathione; D007069:Ifosfamide