Methyl isobutyl ketone (MIBK) induction of α2u-globulin nephropathy in male, but not female rats

Male F-344 rats were administered corn oil (vehicle control), d-limonene (positive control, 300 mg/kg), or MIBK (1000 mg/kg) and female F-344 rats corn oil (vehicle control) or MIBK for 10 consecutive days by oral gavage. Approximately 24 h after the final dose the kidneys were excised and the left kidney prepared and evaluated for histological changes including protein (hyaline) droplet accumulation, immunohistochemical staining for alpha 2u-globulin (alpha 2u), and proliferating cell nuclear antigen (PCNA) to quantitate renal cell proliferation. The right kidney was prepared for quantitation of total protein and alpha 2u using an ELISA. MIBK elicited an increase in protein droplets, accumulation of alpha 2u, and renal cell proliferation in male, but not female rats, responses characteristic of alpha 2u-mediated nephropathy. MIBK produced identical histopathological changes in the male rat kidney when compared to d-limonene, an acknowledged inducer of alpha 2u-nephropathy except that the grade of severity tended to be slightly lower with MIBK. MIBK did not induce any effects in female rats. Therefore, renal histopathology, along with the other measures of alpha 2u accumulation, provides additional weight of evidence to support the inclusion of MIBK in the category of chemicals exerting renal effects through a alpha 2u-nephropathy-mediated mode-of-action. (c) 2009 Elsevier Ireland Ltd. All rights reserved.