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Glutathione Conjugates of tert-Butyl-hydroquinone, a Metabolite of the Urinary Tract Tumor Promoter 3-tert-Butyl-hydroxyanisole, Are Toxic to Kidney and Bladder

Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712 [M. M. C. G. P., M. I. R., T. J. M., S. S. L.], and Department of Biochemical Toxicology, Eli Lilly and Company, Greenfield, Indiana 46140 [T. W. J.]

3-tert-Butyl-4-hydroxyanisole and tert-butyl-hydroquinone (TBHQ) are antioxidants known to promote renal and bladder carcinogenesis in the rat, although the mechanisms of these effects are unclear. Because glutathione (GSH) conjugates of a variety of hydroquinones are nephrotoxic, and because 2-tert-butyl-5-(glutathion-S-yl)hydroquinone [5-(GSyl)-TBHQ], 2-tert-butyl-6-(glutathion-S-yl)hydroquinone [6-(GSyl)TBHQ], and 2-tert-butyl-3,6-bis-(glutathion-S-yl)hydroquinone [3,6-bis-(GSyl)-TBHQ] have been identified recently as metabolites of TBHQ in the male rat, we investigated the effects of these metabolites in the male rat. At the highest dose tested (400 µmol/kg, i.v.) 5-(GSyl)TBHQ and 6-(GSyl)TBHQ caused 2-fold increases in the urinary excretion of -glutamyl transpeptidase and alkaline phosphatase, and pigments arising from the polymerization of metabolites were deposited in the kidney. 3,6-bis-(GSyl)TBHQ (200 µmol/kg) was the most potent of the GSH conjugates tested and produced significant increases in the urinary excretion of -glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, and glucose (2-, 2-, 22-, and 11-fold increases, respectively). Alterations in the biochemical parameters correlated with the degree of single cell and tubular necrosis in the S₃-M segment of the proximal tubule, as observed by light microscopy. In addition to nephrotoxicity, 3,6-bis-(GSyl)TBHQ increased the bladder wet weight 2-fold and caused severe hemorrhaging of the bladder. The half-wave oxidation potentials of 5-(GSyl)TBHQ and 6-(GSyl)TBHQ were similar to that of TBHQ, whereas the half-wave oxidation potential of 3,6-bis-(GSyl)TBHQ was 100 mV higher than that of TBHQ. The TBHQ-GSH conjugates also catalyzed the formation of 8-hydroxydeoxyguanosine, indicating that GSH conjugation does not impair the redox activity of TBHQ. Because some chemicals may induce carcinogenesis by a mechanism involving cytotoxicity followed by sustained regenerative hyperplasia, our results suggest that the toxicity of GSH conjugates of TBHQ to kidney and bladder may contribute to the promoting effect of 3-tert-butyl-4-hydroxyanisole and TBHQ in these tissues.

¹ Present address: Royal Shell Laboratory Amsterdam, Badhuisweg 3, 1031 CM Amsterdam, the Netherlands.

² Present address: Laboratory of Drug Discovery Research and Development, National Cancer Institute, Frederick Cancer Research and Development Center, Building 1052, Frederick, MD 21702-1201.

³ To whom requests for reprints should be addressed, at Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, TX 78712. Phone: (512) 471-5190; Fax: (512) 471-5002; E-mail: slav@uts.cc.utexas.edu.

Received 9/ 6/95. Accepted 1/ 2/96.

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