Measurement of Nuclear DNA Modification by 32P-Postlabeling in the Kidneys of Male and Female Fischer 344 Rats after Multiple Gavage Doses of Hydroquinone

Abstract

Measurement of Nuclear DNA Modification by 32P-Postlabeling in the Kidneys of Male and Female Fischer 344 Rats after Multiple Garage Doses of Hydroquinone. English, J. C., Hill, T., O'Donoghue, J. L., and Reddy, M. V. (1994). Fundam. Appl. Toxicol. 23, 391-396.Oral administration of hydroquinone (HQ) to male Fischer 344 (F344) rats results in dose-related kidney toxicity beginning with mild enzymuria by 1 week, significant cell proliferation by 6 weeks, and nephropathy and an increase in the incidence of renal tubule adenomas after 2 years. Female F344 rats, B6C3F1 mice, Sprague-Dawley rats, dogs, and humans are resistant to the renal toxicity of HQ associated with repeated exposure. To determine the potential of HQ to induce covalent DNA adducts in the kidney, male and female F344 rats were given 0, 2.5, 25, or 50 mg/kg HQ by gavage for 6 weeks, and nuclear DNA isolated from kidneys was analyzed by the 32 P-postlabeling assay. At 50 mg/kg, males, but not females, showed an increase in the rate of excretion of N -acetyl-β-d-glucosaminidase, indicative of proximal tubular damage. Analysis of nuclear DNA preparations by the postlabeling assay showed that HQ does not produce covalent DNA adducts in the kidneys of male and female rats. The assay's lower limit of detection is 1 adduct in 109 to 1010 DNA nucleotides. No treatment-related increases in background radioactivity levels on the chromatograms were seen at locations corresponding to the major in vitro adducts of HQ and p-benzoquinone. HQ treatment, however, resulted in the reduction of the levels of certain endogenous adducts (I-compounds), the biological significance of which is unknown. The results indicate that HQ does not produce covalent DNA adducts in the kidneys of male and female rats after repeated oral administration at nephrotoxic dose levels, and suggest a nongenotoxic etiology of benign tumors in the kidneys of male F344 rats treated with HQ.