title: Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR alpha/gamma agonist: Evidence for urolithiasis as the inciting event in the mode of action.
abstract: Muraglitazar, a PPARalpha/gamma 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 > or = 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.
authors.affiliation: Department of Drug Safety Evaluation, Bristol-Myers Squibb Co., Evansville, Indiana 47721, USA. mark.dominick@bms.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dominick
authors.forename: Melvin R
authors.initials: MR
authors.lastname: White
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sanderson
authors.forename: Terry
authors.initials: T
authors.lastname: Van Vleet
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Lora E
authors.initials: LE
authors.lastname: Arnold
authors.forename: Marty
authors.initials: M
authors.lastname: Cano
authors.forename: Sarah
authors.initials: S
authors.lastname: Tannehill-Gregg
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Moehlenkamp
authors.forename: Crystal R
authors.initials: CR
authors.lastname: Waites
authors.forename: Beth E
authors.initials: BE
authors.lastname: Schilling
mesh_terms: D000818:Animals; D000963:Antimetabolites; D017209:Apoptosis / Q000187:drug effects; D019540:Area Under Curve; D001973:Bromodeoxyuridine; D002118:Calcium / Q000652:urine; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D002951:Citrates / Q000652:urine; D004573:Electrolytes / Q000652:urine; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D008297:Male; D008855:Microscopy, Electron, Scanning; D009929:Organ Size; D010070:Oxalates / Q000652:urine; D010080:Oxazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010710:Phosphates / Q000652:urine; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley; D013052:Spectrometry, X-Ray Emission; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000473:pathology*; D052878:Urolithiasis / Q000139:chemically induced* / Q000473:pathology*; D019459:Urothelium / Q000473:pathology*
chemical_list: D000963:Antimetabolites; D002273:Carcinogens; D002951:Citrates; D004573:Electrolytes; D010070:Oxalates; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D010710:Phosphates; D001973:Bromodeoxyuridine; D002118:Calcium; D005998:Glycine; C500085:muraglitazar