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Urothelial Carcinogenesis in the Urinary Bladder of Male Rats Treated with Muraglitazar, a PPAR/ Agonist: Evidence for Urolithiasis as the Inciting Event in the Mode of Action

¹ Department of Drug Safety Evaluation, Bristol-Myers Squibb Co., Evansville, Indiana 47721, USA
² Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA

Correspondence: Address correspondence to: Mark A. Dominick, 2400 W. Lloyd Expressway, P3, Evansville, IN 47721, USA; e-mail:mark.dominick{at}bms.com

Muraglitazar, a PPAR/ agonist, dose-dependently increased urinary bladder tumors in male Harlan Sprague–Dawley (HSD) rats administered 5, 30, or 50 mg/kg/day for up to 2 years. To determine the mode of tumor development, male HSD rats were treated daily for up to 21 months at doses of 0, 1, or 50 mg/kg while being fed either a normal or 1% NH₄Cl-acidified diet. Muraglitazar-associated, time-dependent changes in urine composition, urothelial mitogenesis and apoptosis, and urothelial morphology were assessed. In control and treated rats fed a normal diet, urine pH was generally 6.5, which facilitates formation of calcium- and magnesium-containing solids, particularly in the presence of other prolithogenic changes in rat urine. Urinary citrate, an inhibitor of lithogenesis, and soluble calcium concentrations were dose dependently decreased in association with increased calcium phosphate precipitate, crystals and/or microcalculi; magnesium ammonium phosphate crystals and aggregates; and calcium oxalate-containing thin, rod-like crystals. Morphologically, sustained urothelial cytotoxicity and proliferation with a ventral bladder predilection were noted in treated rats by month 1 and urinary carcinomas with a similar distribution occurred by month 9. Urothelial apoptotic rates were unaffected by muraglitazar treatment or diet. In muraglitazar-treated rats fed an acidified diet, urine pH was invariably < 6.5, which inhibited formation of calcium- and magnesium-containing solids. Moreover, dietary acidification prevented the urothelial cytotoxic, proliferative, and tumorigenic responses. Collectively, these data support an indirect pharmacologic mode of urinary bladder tumor development involving alterations in urine composition that predispose to urolithiasis and associated decreases in urine-soluble calcium concentrations.

Key Words: Dual PPAR/ agonist • urothelial • urinary bladder • carcinogenesis • urolithiasis • hypocalciuria

Abbreviations: AGT, alanine glyoxalate aminotransferase • AUC, area under the curve • BrdU, aromodeoxyuridine • C-DIM, 1, 1-bis (3'-indolyl)-1-(p-substituted phenyl) methanes • dUTP, aeoxyuridine triphosphate • EGF, epidermal growth factor • FDA, Federal Drug Administration • GAO, glycolate oxidase • HSD, Harlan Sprague–Dawley • IP, intraperitoneal • LDH, lactate dehydrogenase • mRNA, messenger ribonucleic acid • NaDC-1, sodium dicarboxylate cotransporter • NCI, National Cancer Institute • PEG, polyethylene glycol • PPAR, peroxisome proliferator activated receptor • PPRE, peroxisome proliferator response element • RXR, retinoid X receptor • SD, standard deviation • SD rats, Sprague-Dawley rats • SEM, scanning electronic microscopy • TCA, tricarboxylic acid • THP, Tamm-Horsfall protein • TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling • XDS, energy dispersive X-ray spectroscopy

Toxicologic Pathology, Vol. 34, No. 7, 903-920 (2006)
DOI: 10.1080/01926230601072327


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