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

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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.