Protective effect of an intrinsic antioxidant, HMH (5-hydroxy-1-methylhydantoin; NZ-419), against cellular damage of kidney tubules

• Published in: Experimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie Vol. 65; no. 5; pp. 559 - 566
• Main Authors: Ienaga, Kazuharu, Park, Chan Hum, Yokozawa, Takako
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.07.2013
• Subjects: Animals; antioxidant activity; antioxidants; Antioxidants - adverse effects; Antioxidants - chemistry; Antioxidants - pharmacology; Cell Culture Techniques; Cell Hypoxia; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Membrane - pathology; cephaloridine; Cephaloridine - toxicity; cisplatin; Cisplatin - toxicity; creatinine; Creatinine metabolite; Dose-Response Relationship, Drug; epithelial cells; HMH (NZ-419); Humans; Hydantoins - adverse effects; Hydantoins - chemistry; Hydantoins - pharmacology; hydroxyl radicals; hypoxia; Intrinsic antioxidant; kidney diseases; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Kidney Tubules - pathology; lactate dehydrogenase; LDH; Lipid Peroxidation - drug effects; LLC-PK1 Cells; malondialdehyde; MDA; metabolites; Molecular Structure; peroxidation; protective effect; rats; Reactive Oxygen Species - metabolism; renal tubules; signal transduction; Swine; Tubular cell injury; xenobiotics; LDH; HMH (NZ-419); Tubular cell injury; MDA; LLC-PK1 cells; Intrinsic antioxidant; Creatinine metabolite
• ISSN: 0940-2993; 1618-1433
• DOI: 10.1016/j.etp.2012.05.001

HMH (5-hydroxy-1-methylhydantoin; NZ-419) is a mammalian creatinine metabolite and an intrinsic antioxidant. HMH prevents the progression of chronic kidney disease in rats when a sufficient amount is taken orally. We assessed whether intrinsic and higher levels of HMH could protect tubular epithelial cells, LLC-PK1 cells, against known cellular damage caused by xenobiotics, such as cisplatin and cephaloridine, or by hypoxia/reoxygenation treatment. Both cell damage and peroxidation, monitored as the leakage of lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively, from cells into the media, were inhibited by HMH in a concentration-dependent manner. The minimum effective concentration of HMH (2.5μM) seemed to be too low for HMH to only be a direct hydroxyl radical scavenger. Additional antioxidant effect(s) inhibiting reactive oxygen species generation and/or modulating signal transduction pathways were suggested. The possibility that intrinsic HMH could be a protectant for the kidney was indicated. At the same time, for sufficient inhibition, higher concentrations than intrinsic HMH concentrations may be necessary. Patterns of efficacies of HMH on LDH and MDA against different kinds of cellular damage were compared with our reported data on those of corresponding, naturally occurring antioxidants. A common and specific inhibitory mechanism as well as common target(s) in kidney injuries were indicated.