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

工作总结：α-2u-球蛋白 一种假说已被用来否定肾脏与人类的相关性， 在雄性大鼠中诱发肿瘤。我们正在研究 在这一假设中，关键的生物过程之间的联系， 使用公布的数据进行模型模拟。该模型包括 描述结合的毒性的参数值 配体，其与α-2u-球蛋白的相互作用， 来自肝脏的α-2u-球蛋白，α-2u-球蛋白的再吸收 进入近曲小管上皮细胞， 配体-α-2u-球蛋白复合物。一个生理学模型， 2，2，4-三甲基戊-2-醇（TMP-2-OH）对 α-2u-球蛋白在雄性大鼠肾脏中的蓄积表明， 这种作用不能仅仅是由于蛋白水解的抑制。的 模型可以再现血液和肾脏的时间过程数据 TMP-2- OH和肾α-2u-球蛋白浓度，如果 肝脏α-2u-球蛋白合成的一过性增加， 由血液中的配体α-2u-球蛋白刺激， 假设。该模型表明，α-2u-球蛋白配体可能 增加这种蛋白质肝合成和 未结合的A2 U-球蛋白也可能由于以下原因而减少 配体的积累。

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.