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

工作总结：阿尔法-2U-球蛋白假说已经被用来打消人类诱发雄性大鼠肾肿瘤的相关性。在这一假说中，我们正在使用已公布的数据通过模型模拟来检验关键生物过程之间的定量联系。该模型包括描述结合配体的毒代动力学、其与α-2U-球蛋白的相互作用、从肝脏分泌α-2U-球蛋白、α-2U-球蛋白被近端肾小管上皮细胞吸收以及配体-α-2U-球蛋白复合体的降解的参数值。2，2，4-三甲基戊烷-2-醇(TMP-2-OH)对雄性大鼠肾脏α-2U-球蛋白蓄积影响的生理模型表明，这种作用不能仅仅归因于抑制蛋白分解。如果假设肝脏合成α-2U球蛋白的一过性增加，则该模型可以再现血液和肾脏TMP-2-OH和肾脏α-2U-球蛋白浓度的时程数据。该模型表明，α-2U-球蛋白配体可能会增加肝脏对该蛋白质的合成。该模型预测，与没有α-2U球蛋白相比，配体更多地输送到肾脏，肾脏产生更多潜在的有毒代谢物。分析表明，诱导的溶酶体活性和有毒代谢产物的增加可能是导致α-2U-球蛋白配体肾毒性的原因之一。-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