The use of 13C-labelling to prove that creatinine is oxidized by mammals into creatol and 5-hydroxy-1-methylhydantoin

Ienaga, Kazuharu; Nakamura, Ko; Yamakawa, Masanori; Toyomaki, Yoshio; Matsuura, Hirohide; Yokozawa, Takako; Oura, Hikokíchi; Nakano, Koji

doi:10.1039/c39910000509

Cited by 31 publications

(20 citation statements)

References 8 publications

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“…[1][2][3] Studies revealed that the liver and the kidneys oxidize CTN into creatol, which is converted into MG. [4][5][6][7] Oxidation of CTN with active oxygen (e.g., hydrogen peroxide) was proven to generate MG, whereas scavengers of active oxygen (e.g., glutathione, sorbitol) considerably reduced MG synthesis. 8 MG is expelled mainly from the kidney and is considered as not only a neurotoxin [9][10][11] but also a critical uremic toxin.…”

Section: Introductionmentioning

confidence: 99%

Methylguanidine cytotoxicity on HK-2 cells and protective effect of antioxidants against MG-induced apoptosis in renal proximal tubular cellsin vitro

et al. 2010

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The present study was designed to explore the toxic effect of MG on renal proximal tubular cells as well as the protective effect of antioxidants PGE1 and probucol against MG-induced apoptosis in renal proximal tubular cells. HK-2 cells were used as the subject. The cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. N-Acetyl-3-D-glucosaminidase (NAG) activity, malondialdehyde (MDA) content, and superoxide dismutase (SOD) activity were determined. Cell apoptosis was determined by flow cytometry (light scatter and propidium iodide/annexin V-FTC fluorescence) and by nuclear staining with Hoechst 33258. Cells were exposed to MG (0.25, 0.5, or 1 mmol/L), MG (0.5 mmol/L) + PGE1 (2 μg/L), and MG (0.5 mmol/L) + probucol (20 μmol/L) respectively for 24 h. MG induced a significant dose-dependent loss of cell viability. Both PGE1 and probucol improved the viability of MG-treated HK-2 cells. Cells showed apoptotic morphology (deepened stain, karyopyknosis, and apoptotic body) when exposed to 0.5 mmol/L MG for 24 h, and the apoptosis ratio was increased compared with the control. The presence of PGE1 or probucol significantly lowered the apoptotic ratio. Moreover, PGE1 or probucol notably decreased the MDA content and increased the SOD activity compared with when the cells were treated with MG only. The results of the present study clearly demonstrate that MG could promote apoptosis of renal proximal tubular cells in vitro. Both PGE1 and probucol could protect renal proximal tubular cells from MG-induced apoptosis.

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Section: Introductionmentioning

confidence: 99%

Methylguanidine cytotoxicity on HK-2 cells and protective effect of antioxidants against MG-induced apoptosis in renal proximal tubular cellsin vitro

et al. 2010

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“…1) In our previous paper, 3) we reported for the first time that an intrinsic antioxidant compound could prevent the initiation and/or progression of CRF: the compound investigated was NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione, 5-hydroxy-1-methylhydantoin: HMH, CAS: 84210-26-4), [4][5][6][7][8][9] a creatinine (Cr) metabolite that prevented the initiation and/or progression of adenine-induced CRF. We chose CRF or CKD at stages equivalent to human stages 3, 4 and 5, where hydroxyl radicals are over-produced, 2,10) as one of the targets aims, 3,11,12) because NZ-419 had been shown to be a hydroxyl radical scavenger.…”

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confidence: 99%

Treatment with NZ-419 (5-Hydroxy-1-methylimidazoline-2,4-dione), a Novel Intrinsic Antioxidant, against the Progression of Chronic Kidney Disease at Stages 3 and 4 in Rats

Ienaga

Yokozawa

2010

Biological & Pharmaceutical Bulletin

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For rats, glomerular filtration rate (GFR) and its relative GFR (ratio to normal GFR 0 ) were estimated in order to classify their chronic kidney disease (CKD) into 5 stages like those in humans. The adenine-loaded rats, which were used to show the intrinsic antioxidant and creatinine (Cr) metabolite, NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione), when taken orally, prevented the progression of chronic renal failure (CRF), were used as a model to reach the severest stage 5. In this report, we show that, by using both a tubular lesion and a glomerular lesion models (adenine-loaded and 5/6 nephrectomized rats, respectively), peroral NZ-419 might be a common tool to prevent the progression of CRF at CKD stages 3 and 4 under the condition that most rats in the control group still remained at stage 4 (0.15Ͻ ϽGFR/GFR 0 Ͻ Ͻ0.29) at the last. At the minimum effective dose (MED: 100 mg/kg/d) of NZ-419 in adenine-loaded rats, serum Cr and all oxidative stress markers were ameliorated. Two doses (80, 160 mg/kg/d), at around the MED, used for 5/6 nephrectomized rats with a similar CRF severity, gave significant inhibitory effects against the increases in blood urea nitrogen, decreases in renal blood flow and renal plasma flow, and nephrotic syndrome. Oxidative stress markers, the urinary methylguanidine and serum albumin level, were significantly ameliorated.

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“…In addi tion, Cr is a precursor of methylguanidine. Cr is also considered to be a marker of uremic toxins (43)(44)(45)(46). The rats subjected to ischemia-reperfusion showed large increases in the levels of both urea nitrogen and Cr, indicating pathological damage that affected renal function had been caused by ischemia-reperfusion.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of the BuOH Fraction from Mustard Leaf in a Renal Ischemia-Reperfusion Model.

Yokozawa

Kim

Cho

et al. 2002

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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SummaryThe effects of the BuOH fraction from mustard leaf in rats subjected to renal ischemia-reperfusion were examined. The elevated serum superoxide anion (O2-) level and renal xanthine oxidase (XOD) activity in rats subjected to 6-h reperfusion following 1-h is chemia significantly and dose-dependently declined after oral administration of the BuOH fraction at doses of 50 and 200 mg/kg body weight/d for 10 d prior to ischemia-reperfusion. These findings indicate that this fraction might scavenge O2 or inhibit the generation of O 2 through XOD activated by the ischemia-reperfusion process. In addition, the thiobarbi turic acid-reactive substance level of the renal mitochondrial fraction of rats given the BuOH fraction orally was significantly lower than that of control rats given physiological saline (vehicle), implying that this fraction exerted protective action against lipid peroxidation caused by ischemia-reperfusion. Furthermore, oral administration of the BuOH fraction re duced the serum urea nitrogen and creatinine levels, indicators of renal function. These re sults suggest that the BuOH fraction has protective effects against ischemia-reperfusion in jury, acting as an antioxidant by scavenging O2-, inhibiting O2-generation through XOD, protecting against lipid peroxidation and ameliorating renal functional impairment.

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The use of 13C-labelling to prove that creatinine is oxidized by mammals into creatol and 5-hydroxy-1-methylhydantoin

Cited by 31 publications

References 8 publications

Methylguanidine cytotoxicity on HK-2 cells and protective effect of antioxidants against MG-induced apoptosis in renal proximal tubular cellsin vitro

Methylguanidine cytotoxicity on HK-2 cells and protective effect of antioxidants against MG-induced apoptosis in renal proximal tubular cellsin vitro

Treatment with NZ-419 (5-Hydroxy-1-methylimidazoline-2,4-dione), a Novel Intrinsic Antioxidant, against the Progression of Chronic Kidney Disease at Stages 3 and 4 in Rats

Protective Effects of the BuOH Fraction from Mustard Leaf in a Renal Ischemia-Reperfusion Model.

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