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

工作总结：a2u球蛋白假说已被用来打折 诱发雄性大鼠肾肿瘤与人类的相关性。我们是 研究关键生物过程之间的定量联系 这一假设是通过使用公布的数据进行模型模拟得出的。模型 包括描述结合的毒代动力学的参数值 配体，它与a2u球蛋白的相互作用，a2u球蛋白的分泌 从肝脏，a2u球蛋白被吸收到近端小管 上皮细胞，以及配体-a2u-球蛋白复合体的降解。一个 2，2，4-三甲基戊烷-2-醇(TMP)作用的初步模型 雄性大鼠肾脏中a2u球蛋白的积累表明，这 效果不能仅仅归因于抑制蛋白质分解。模型 提示a2u-球蛋白配体可能促进肝脏合成 这种蛋白质和未结合a2u球蛋白的降解也可能是 由于配基的积累而减少的。

Summary of Work: The a2u-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 a2u-globulin, secretion of a2u-globulin from the liver, resorption of a2u-globulin into proximal tubule epithelial cells, and degradation of the ligand-a2u-globulin complex. A preliminary model of the effects of 2,2,4-trimethylpentan-2-ol (TMP) on the accumulation of a2u-globulin in the male rat kidney showed that this effect cannot be due solely to inhibition of proteolysis. The model suggests that a2u-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.