Detection of maleate-induced Fanconi syndrome by decreasing accumulation of125I-3-iodo-a-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice: A trial of separate evaluation of reabsorption

Shikano, Naoto; Kotani, Takashi; Itoh, Yoichi; Ishikawa, Nobuyoshi; Kawai, Keiichi; Nakajima, Syuichi; Yoshimoto, Mitsuyoshi; Nishii, Ryuichi; Flores, Leo G.; Saji, Hideo

doi:10.1007/bf03027427

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…Maleate, which induces mitochondrial dysfunction (Bank et al 1986;Kramer and Gonick 1970), produces a generalized tubular transport defect closely resembling Fanconi syndrome in experimental animal models (Shikano et al 2006), and results in a decreased GFR and renin release (Arend et al 1986). Notably, decreased activity of the renin-angiotensin-aldosterone system has been observed in numerous patients with methylmalonic aciduria and CRF (D_Angio et al 1991); however, patients with methylmalonic aciduria do not present with a Fanconi-like tubulopathy (Walter et al 1989).…”

Section: Kidneymentioning

confidence: 95%

Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

Morath

Okun

Müller

et al. 2007

J of Inher Metab Disea

121

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In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called 'toxic metabolite' hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites ('trapping' hypothesis') is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

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Section: Kidneymentioning

confidence: 95%

Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

Morath

Okun

Müller

et al. 2007

J of Inher Metab Disea

121

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“…The ocular safety of excipient maleic acid following intravitreal injection was assessed in rabbits [2]; the data suggest that maleic acid is toxic to the eyes of rabbits in a concentration-dependent manner. Maleic acid is also a nephrotoxin, causing glycosuria, phosphaturia, and aminoaciduria [5,6,7]. The renal glycosuria, phosphaturia, and aminoaciduria induced by maleic acid are similar to a congenital defect in humans known as Fanconi syndrome, a generalized proximal tubular reabsorptive dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Maleic Acid as a Food Adulterant Determined by Microdialysis in Rat Blood and Kidney Cortex

Hou¹,

Lu²,

Lin³

et al. 2016

Molecules

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Maleic acid has been shown to be used as a food adulterant in the production of modified starch by the Taiwan Food and Drug Administration. Due to the potential toxicity of maleic acid to the kidneys, this study aimed to develop an analytical method to investigate the pharmacokinetics of maleic acid in rat blood and kidney cortex. Multiple microdialysis probes were simultaneously inserted into the jugular vein and the kidney cortex for sampling after maleic acid administration (10 or 30 mg/kg, i.v., respectively). The pharmacokinetic results demonstrated that maleic acid produced a linear pharmacokinetic phenomenon within the doses of 10 and 30 mg/kg. The area under concentration versus time curve (AUC) of the maleic acid in kidney cortex was 5-fold higher than that in the blood after maleic acid administration (10 and 30 mg/kg, i.v., respectively), indicating that greater accumulation of maleic acid occurred in the rat kidney.

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“…Published work reported that exposure to high doses of MA result in phenotypic manifestations such as alopecia and significant decreases in both absolute and relative organ weights (Burnett et al, ). Upon consumption, the absorbed and metabolized MA become nephrotoxic and cause symptoms such as phosphaturia, glycosuria, low molecular weight proteinuria, metabolic acidosis and aminoaciduria (Castano, Marzabal, Casado, Felipe, & Pastor‐Anglada, ; Shikano et al, ). The aforementioned damages to the proximal renal tubules of the kidney, collectively known as Fanconi syndrome, can result in cell necrosis and renal tubular injury in the proximal tubules (Bunton, Fuller, Perry, & Shiner, ).…”

Section: Introductionmentioning

confidence: 99%

Nuclear magnetic resonance‐ and mass spectrometry‐based metabolomics to study maleic acid toxicity from repeated dose exposure in rats

Chen

et al. 2017

J of Applied Toxicology

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Maleic acid (MA), a chemical intermediate used in many consumer and industrial products, was intentionally adulterated in a variety of starch-based foods and instigated food safety incidents in Asia. We aim to elucidate possible mechanisms of MA toxicity after repeated exposure by (1) determining the changes of metabolic profile using H nuclear magnetic resonance spectroscopy and multivariate analysis, and (2) investigating the occurrence of oxidative stress using liquid chromatography tandem mass spectrometry by using Sprague-Dawley rat urine samples. Adult male rats were subjected to a 28 day subchronic study (0, 6, 20 and 60 mg kg ) via oral gavage. Urine was collected twice a day on days 0, 7, 14, 21 and 28; organs underwent histopathological examination. Changes in body weight and relative kidney weights in medium- and high-dose groups were significantly different compared to controls. Morphological alterations were evident in the kidneys and liver. Metabolomic results demonstrated that MA exposure increases the urinary concentrations of 8-hydroxy-2'-deoxyguanosine, 8-nitroguanine and 8-iso-prostaglandin F ; levels of acetoacetate, hippurate, alanine and acetate demonstrated time- and dose-dependent variations in the treatment groups. Findings suggest that MA consumption escalates oxidative damage, membrane lipid destruction and disrupt energy metabolism. These aforementioned changes in biomarkers and endogenous metabolites elucidate and assist in characterizing the possible mechanisms by which MA induces nephro- and hepatotoxicity.

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Detection of maleate-induced Fanconi syndrome by decreasing accumulation of125I-3-iodo-a-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice: A trial of separate evaluation of reabsorption

Abstract: Decreased accumulation of 123I-IMT in the S1 region appears to represent a useful marker for detection of MAL-induced Fanconi syndrome. In future, we plan to assess the efficacy of using 125I-IMT to monitor renal dysfunction induced by nephrotoxic clinical drugs.

Cited by 5 publications

References 21 publications

Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

Pharmacokinetics of Maleic Acid as a Food Adulterant Determined by Microdialysis in Rat Blood and Kidney Cortex

Nuclear magnetic resonance‐ and mass spectrometry‐based metabolomics to study maleic acid toxicity from repeated dose exposure in rats

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