MECHANISM-BASED MODELING OF ALPHA-2U-GLOBULIN ACCUMULATION IN MALE RAT KIDNEY

工作总结：α-2U-球蛋白 假说已经被用来贬低肾脏与人类的相关性。 在雄性大鼠体内诱发肿瘤。我们正在检查数量 在这一假说中，关键生物过程之间的联系 使用发布的数据进行模型模拟。该模型包括 描述结合的毒代动力学的参数值 配体及其与α-2U-球蛋白的相互作用，分泌 肝脏中的α-2U球蛋白、α-2U球蛋白的吸收 转化为近端小管上皮细胞，并降解 配体-α-2U-球蛋白复合体。大鼠的一种生理学模型 2，2，4-三甲基戊烷-2-醇(TMP-2-OH)对人血清白蛋白的影响 α-2U球蛋白在雄性大鼠肾脏中的蓄积 这种效果不能完全归因于抑制蛋白质分解。这个 模型可以再现血液和肾脏的时程数据 TMP-2-OH和肾脏α-2U球蛋白浓度 肝脏合成α-2U球蛋白的一过性增加， 受到血液中连接的α-2U球蛋白的刺激， 假设如此。该模型表明，α-2U球蛋白配体可能 增加肝脏对这种蛋白质的合成和降解 未结合的a2u球蛋白也可能因以下原因而减少 配基的积累。

Summary of Work: The alpha-2u-globulin hypothesis has been used to discount the human relevance of kidney tumors induced in male rats. We are examining quantitative linkages among critical biological processes in this hypothesis by model simulations using published data. The model includes parameter values that describe the toxicokinetics of the binding ligand, its interaction with alpha-2u-globulin, secretion of alpha-2u-globulin from the liver, resorption of alpha-2u-globulin into proximal tubule epithelial cells, and degradation of the ligand-alpha-2u-globulin complex. A physiological model of the effects of 2,2,4-trimethylpentan-2-ol (TMP-2-OH) on the accumulation of alpha-2u-globulin in the male rat kidney showed that this effect cannot be due solely to inhibition of proteolysis. The model could reproduce time course data of blood and kidney TMP-2- OH and renal alpha-2u-globulin concentrations if a transient increase in hepatic synthesis of alpha-2u-globulin, stimulated by liganded alpha-2u-globulin in the blood, was assumed. The model suggests that alpha-2u-globulin ligands may increase the hepatic synthesis of this protein and that degradation of unbound a2u-globulin may also be reduced as a consequence of accumulation of the ligand.