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

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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.