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Repair of O⁶-Methylguanine and O⁴-Methylthymidine in F344 Rat Liver following Treatment with 1,2-Dimethylhydrazine and O⁶-Benzylguanine

Departments of Environmental Sciences and Engineering [S. M. O., J. A. S.], and Pathology [J. A. S.], University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, and Departments of Cellular and Molecular Physiology and of Pharmacology, Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033 [A. E. P.]

Concentrations of O⁶-methylguanine, O⁴-methylthymidine, and N-7-methylguanine were measured in the livers of Fischer 344 rats following treatment with 1,2-dimethylhydrazine (20 mg/kg, s.c.) alone or in combination with the O⁶-alkylguanine transferase inhibitor O⁶-benzylguanine (100 mg/kg, i.p., daily). Animals were sacrificed at 12, 24, 36, or 48 h following 1,2-dimethylhydrazine exposure. Direct measurement of alkyltransferase demonstrated that daily treatment with O⁶-benzylguanine completely eliminated detectable alkyltransferase activity in the livers of treated rats. Adducts in liver DNA were quantitated by high performance liquid chromatography separation followed by fluorescence detection, UV absorbance, and/or specific radioimmunological assays. In animals exposed to 1,2-dimethylhydrazine alone O⁶-methylguanine concentrations declined rapidly, whereas animals exposed to both O⁶-benzylguanine and 1,2-dimethylhydrazine showed less removal of O⁶-methylguanine, with significant differences between the two populations appearing at 36 and 48 h. O⁴-Methylthymidine removal also differed significantly between the two groups, with O⁶-benzylguanine-treated animals exhibiting higher concentrations of adducts at 36 and 48 h. O⁶-Benzylguanine treatment had no effect on the removal of N-7-methylguanine. These results show that the rate of disappearance of both O⁶-methylguanine and O⁴-methylthymidine is slower following alkyltransferase depletion, suggesting that mammalian alkyltransferase is involved in the removal of O⁴-methylthymidine lesions as well as O⁶-methylguanine lesions.

¹ To whom requests for reprints should be addressed, at Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Campus Box 7400, Chapel Hill, NC 27599.

Received 2/15/93. Accepted 6/22/93.

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