Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR α/γ agonist:: Evidence for urolithiasis as the inciting event in the mode of action
Urothelial carcinogenesis in the urinary bladder of male rats treated with muraglitazar, a PPAR α/γ agonist:: Evidence for urolithiasis as the inciting event in the mode of action
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DOI：
10.1080/01926230601072327
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发表时间：
2006-01-01
影响因子：
1.5
通讯作者：
Schilling, Beth E.
中科院分区：
文献类型：
--
作者：
Dominick, Mark A.;White, Melvin R.;Schilling, Beth E.
PPARα/伽马激动剂Muraglitazar以剂量依赖的方式增加雄性Harlan Spraogue-Dawley(HSD)大鼠的膀胱肿瘤，每天服用5、30或50 mg/kg，最长达2年。为了确定肿瘤的发展模式，雄性HSD大鼠每天以0、1或50 mg/kg的剂量治疗长达21个月，同时喂以正常或1%的NH4<；Cl-酸化饲料。评估了尿液成分、尿路上皮细胞有丝分裂和细胞凋亡以及尿路上皮形态的随时间变化的与莫格列塔相关的变化。在喂食正常饮食的对照组和治疗组大鼠，尿液pH值一般为-gt；=6.5，这有助于形成含钙和镁的固体，特别是在大鼠尿液中存在其他促结石变化的情况下。随着磷酸钙沉淀物、晶体和/或微结石、磷酸镁铵晶体和聚集体以及含有草酸钙的细长棒状晶体的增加，尿柠檬酸盐(一种结石形成的抑制物)和可溶性钙浓度呈剂量依赖性下降。从形态上看，治疗1个月的大鼠出现持续的尿路上皮细胞毒性和增殖，并伴有腹侧膀胱倾向，9个月时出现类似分布的尿路癌。莫格列塔治疗或饮食对尿路上皮细胞凋亡率无影响。服用莫格列塔的大鼠喂食酸化饮食后，尿液pH值始终为-6.5，这抑制了含有钙和镁的固体的形成。此外，饮食酸化可防止尿路上皮细胞毒性、增殖和致瘤反应。总而言之，这些数据支持膀胱肿瘤发生的间接药理学模式，包括尿液成分的改变，从而易患尿石症，并伴随尿液可溶钙浓度的降低。
Muraglitazar, a PPAR alpha/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% NH4 < Cl-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.