title: Detection of maleate-induced Fanconi syndrome by decreasing accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine in the proximal tubule segment-1 region of renal cortex in mice: a trial of separate evaluation of reabsorption.
abstract: OBJECTIVE
  Fanconi syndrome is a renal dysfunction characterized by various combinations of renal tubular transport dysfunction involving amino acids, glucose, protein and other substances. Most reabsorption of amino acids occurs in proximal renal tubule segment 1 (S1). The present study evaluated the possibility of early detection of drug-induced Fanconi syndrome, based on decreased renal accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine (125I-IMT), an amino acid transport marker, in the S1 region of renal cortex. The present experimental model used maleate (MAL)-induced Fanconi syndrome in mice. Results were compared between 125I-IMT and 3 other clinical renal radiopharmaceuticals: 99mTc-2,3-dimercaptosuccinic acid (99mTc-DMSA); 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3); and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA).
  
  
  METHODS
  Male ddY mice (age, 6 weeks; body weight, 25 g) were used to create a Fanconi model of renal dysfunction. A single dose of maleate disodium salt was administered by intraperitoneal injection (6 mmol/kg). Hematoxylin and eosin (HE) staining of the renal cortex, renal autoradiography and measurement of renal radioactivity of labeled compounds were performed at 30, 60, 90 and 120 min after MAL injection. At 5 min after injection of labeled compounds (18.5 kBq for accumulation experiment, 670 kBq for autoradiography), animals were sacrificed by ether overdose and kidneys were removed. For the accumulation experiment, radioactivity was measured using a well-type scintillation counter. For autoradiography, 20-microm sections of frozen kidney were used with Bio-Imaging Analyzer.
  
  
  RESULTS
  At 30 min after MAL injection, HE staining showed pyknosis in some proximal tubule cells. At that time, accumulations of 125I-IMT and 99mTc-DMSA in the S1 region were approximately 67% and 55% of control levels (p < 0.005). MAL increased accumulation of 99mTc-DTPA in the S1 region, but had no effect on accumulation of 99mTc-MAG3 in the S 1 region.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan. sikano@ipu.ac.jp
authors.forename: Naoto
authors.initials: N
authors.lastname: Shikano
authors.forename: Syuichi
authors.initials: S
authors.lastname: Nakajima
authors.forename: Takashi
authors.initials: T
authors.lastname: Kotani
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Itoh
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishii
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Leo Garcia
authors.initials: LG
authors.lastname: Flores
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000042:Absorption; D000818:Animals; D004195:Disease Models, Animal; D005198:Fanconi Syndrome / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism*; D007672:Kidney Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D008298:Maleates; D008657:Metabolic Clearance Rate; D008781:Methyltyrosines / Q000493:pharmacokinetics*; D051379:Mice; D008815:Mice, Inbred Strains; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D008298:Maleates; D008781:Methyltyrosines; D019275:Radiopharmaceuticals; C030272:maleic acid; C030855:3-iodo-alpha-methyltyrosine