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

工作总结：α - u-球蛋白假说已被用来贬低在雄性大鼠中诱导的肾脏肿瘤的人类相关性。我们正在通过使用已发表的数据进行模型模拟来检查这一假设中关键生物过程之间的定量联系。该模型包括描述结合配体毒性动力学的参数值，它与α -2u-球蛋白的相互作用，α -2u-球蛋白从肝脏分泌，α -2u-球蛋白被近端小管上皮细胞吸收，以及配体- α -2u-球蛋白复合物的降解。2,2,4-三甲基戊烷-2-醇（TMP-2-OH）对雄性大鼠肾脏α -2u-球蛋白积累的影响的生理模型表明，这种影响不能仅仅是由于抑制蛋白质水解。如果假设在血液中配体α -2u-球蛋白刺激下肝脏α -2u-球蛋白合成瞬间增加，该模型可以重现血液和肾脏中tp -2- oh和α -2u-球蛋白浓度的时间过程数据。该模型表明，α -2u-球蛋白配体可能增加肝脏对该蛋白的合成。该模型预测，与缺乏α - u-球蛋白相比，配体向肾脏的递送量和潜在毒性代谢物的肾脏生成量会增加。分析表明，诱导溶酶体活性和毒性代谢物的增加可能有助于α - u-球蛋白配体的肾毒性。-肾癌，α -2u-球蛋白，雄性大鼠，三甲基戊烷，2,4,4-三甲基-2-戊醇，无铅汽油

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 tubuleepithelial 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. The model predicts greater delivery of ligand to the kidney and greater renal production of potentially toxic metabolites than would occur if alpha-2u-globulin was absent. The analysis indicates that induced lysosomal activity and increased production of toxic metabolites may contribute to the nephrotoxicity of alpha-2u-globulin ligands. - kidney cancer, alpha-2u- globulin, male rats, trimethylpentane, 2,4,4-trimethyl-2-pentanol, unleaded gasoline