Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats

Journal Article · Tue Mar 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.01.006· OSTI ID:21535252

Sato, Keiichiro ^[1]; Awasaki, Yasuyuki; Kandori, Hitoshi; Tanakamaru, Zen-yo; Nagai, Hirofumi ^[1]; Baron, David ^[2]; Yamamoto, Masaki ^[1]

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1. Development Research Center, Takeda Pharmaceutical Company Limited, Osaka 532-8686 (Japan)
2. Takeda Global Research and Development Center, Inc., Deerfield, IL 60015 (United States)

Pioglitazone hydrochloride (PIO), a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, was administered orally for 85 weeks at 16 mg/kg/day to male rats fed either a diet containing 1.5% ammonium chloride (acid-forming diet) or a control diet to investigate the effects of urinary acidification induced by the acid-forming diet on the tumorigenic potential of PIO in the urinary bladder. The surviving animals at the end of the administration period were followed to the end of the 2-year study period without changes in the diet and were subjected to terminal necropsy on Week 104. The number of urinary microcrystals, evaluated by manual counting with light microscopy and by an objective method with a laser diffraction particle size analyzer, was increased by PIO on Weeks 12 and 25 and the increases were markedly suppressed by urinary acidification. Urinary citrate was decreased by PIO throughout the study period, but no changes were seen in urinary oxalate at any timepoint. The incidences of PIO-treated males bearing at least one of the advanced proliferative changes consisting of papillary hyperplasia, nodular hyperplasia, papilloma or carcinoma were significantly decreased from 11 of 82 males fed the control diet to 2 of 80 males fed the acid-forming diet. The acid-forming diet did not show any effects on the toxicokinetic parameters of PIO and its metabolites. Microcrystalluria appears to be involved in the development of the advanced stage proliferative lesions in bladder tumorigenesis induced by PIO in male rats.

• OSTI ID: 21535252
• Journal Information: Toxicology and Applied Pharmacology, Vol. 251, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.01.006; PII: S0041-008X(11)00015-9; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ACIDIFICATION
AMMONIUM CHLORIDES
BLADDER
CARCINOMAS
CONTROL
CRYSTALS
DIET
MALES
METABOLITES
PARTICLE SIZE
RATS
RECEPTORS
AMMONIUM COMPOUNDS
AMMONIUM HALIDES
ANIMALS
BODY
CHLORIDES
CHLORINE COMPOUNDS
DISEASES
HALIDES
HALOGEN COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
NEOPLASMS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RODENTS
SIZE
URINARY TRACT
VERTEBRATES