A physiological model for ligand-induced accumulation of alpha 2u globulin in male rat kidney: roles of protein synthesis and lysosomal degradation in the renal dosimetry of 2,4,4-trimethyl-2-pentanol.

ABSTRACT

A physiologically based pharmacokinetic (PBPK) model was constructed for the disposition of 2,4,4-trimethyl-2-pentanol (TMP-2-OH) in male rats and its induction of accumulation of renal alpha2u-globulin (alpha2u). The model included diffusion-restricted delivery of TMP-2-OH to compartments representing liver, lung, fat, kidney, GI tract, aggregated rapidly perfused tissues, and aggregated slowly perfused tissues. Metabolism by oxidation and glucuronidation was included for liver and kidneys. Rates of hepatic alpha2u production and resorption by renal proximal tubules were taken from the literature. Degradation of liganded alpha2u by renal lysosomal cathepsins was modeled with a Km value corresponding to the measured 30% reduction in proteolytic efficiency and with free and bound forms of alpha2u competing for access to the enzymes. Increased pinocytotic uptake of alpha2u into the kidney induces cathepsin activity. A model that ascribed renal alpha2u accumulation solely to reduced lysosomal proteolysis failed to reproduce the observed accumulation. The model could reproduce experimental observations if a transient increase in hepatic synthesis of alpha2u, stimulated by the presence of liganded alpha2u in the blood, and accelerated secretion of the protein from the liver were assumed. This model reproduces time course data of blood and kidney TMP-2-OH and renal alpha2u concentrations, suggesting that renal accumulation of alpha2u is not simply a consequence of reduced proteolytic degradation but may also involve a transient increase in hepatic alpha2u production. The model predicts increased delivery of TMP-2-OH to the kidney and consequent increased renal production of potentially toxic TMP-2-OH metabolites than would be the case if no alpha2u were present. Induced lysosomal activity and increased production of toxic metabolites may both contribute to the nephrotoxicity observed in male rats exposed to an alpha2u ligand or its precursor.