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In Vivo Kinetics of O⁶-Methylguanine and 7-Methylguanine Formation and Persistence in DNA of Rats Treated with Symmetrical Dimethylhydrazine¹

Departments of Community and Environmental Medicine [R. C. S.] and Medical Pharmacology and Therapeutics [D. C. H.] and University of California Southern Occupational Health Center [R. C. S.], University of California, Irvine, College of Medicine, Irvine, California 92717

The rates of appearance and removal of 7-methylguanine and O⁶-methylguanine in DNA from rat liver, kidney, and colon were determined at various intervals up to 120 hr after i.p. administration of 10.2, 40.7, 81.5, or 163 mg 1,2-dimethylhydrazine (SDMH) per kg body weight (one-sixteenth, one-fourth, one-half, or one 50% lethal dose) using high-pressure liquid chromatography and fluorescence spectrophotometry. In most cases, increasing doses of SDMH slowed the rate of methylation of DNA, especially of the liver; colon DNA was methylated at a faster rate than was liver DNA, and kidney DNA was methylated at the slowest rate following SDMH administration. Removal of O⁶-methylguanine was slow (half-life, 37 to 50 hr) when this base was present in liver DNA at concentrations above 400 µmol/mol guanine; as the concentration fell below 300 µmol O⁶-methylguanine per mol guanine, the removal rate more than doubled (half-life, 16 to 19 hr). Some evidence was obtained to suggest that in the first 12 hr after maximum DNA methylation following SDMH administration, a rapid time-dependent removal of 7-methylguanine from liver and kidney but not colon DNA occurred. In these instances, then, the rates of formation and removal of aberrant methylated bases did not follow first-order kinetics.

¹ This investigation was supported by Grant CA-21955 from the National Cancer Institute, NIH, United States Department of Health and Human Services, and by Contract F33615-76-C-5005 from the United States Air Force.

² To whom requests for reprints should be addressed.

Received 5/12/81. Accepted 7/14/81.

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