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Toxicological Sciences 62, 228-235 (2001)
Copyright © 2001 by the Society of Toxicology

CARCINOGENICITY

Characterization of tert-Butyl Alcohol Binding to {alpha}2u-Globulin in F-344 Rats

T. M. Williams and S. J. Borghoff,1

CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709

tert-Butyl alcohol (TBA) is widely used in the manufacturing of certain perfumes, cosmetics, drugs, paint removers, methyl tert-butyl ether (MTBE), and industrial solvents. In both rodents and humans, TBA is a major metabolite of MTBE, an oxygenated fuel additive. Chronic TBA exposure causes protein droplet nephropathy, {alpha}2u-globulin ({alpha}2u) accumulation, renal cell proliferation, and with chronic exposure, renal tumors in male, but not female, rats. These effects suggest an {alpha}2u-mediated mechanism for renal tumors. The objective of the present study was to determine whether TBA or its metabolites bind to {alpha}2u. Mature male and female F-344 rats were administered a single gavage dose of 500 mg/kg TBA, 500 mg/kg 14C-TBA, or corn oil. TBA equivalents/gram or ml of tissue in the male rat kidney, liver, and blood were higher than the levels measured in female rat tissue 12 h after 14C-TBA administration. Gel filtration and anion-exchange chromatography demonstrated that 14C-TBA–derived radioactivity co-eluted with {alpha}2u from male kidney cytosol. Protein dialysis studies demonstrated that the interaction between 14C-TBA–derived radioactivity and {alpha}2u was reversible. Incubations of the low-molecular-weight protein fraction (LMWPF) isolated from 14C-TBA–treated male rat kidneys with d-limonene oxide (a chemical with a high affinity to {alpha}2u) demonstrated that 14C-TBA–derived radioactivity was displaced. Gas chromatography-mass spectrometry analysis confirmed that TBA was present in this LMWPF fraction. These results demonstrate that TBA interacts with {alpha}2u, which explains the accumulation of {alpha}2u in the male rat kidney following TBA exposure.

Key Words: tert-butyl alcohol (TBA); {alpha}2u-globulin ({alpha}2u) nephropathy; male rats; protein binding.


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Amended Final Report of the Safety Assessment of t-Butyl Alcohol as Used in Cosmetics
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