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Kinetics of Formation and Persistence of Ethylguanines in DNA of Rats and Hamsters Treated with Diethylnitrosamine¹

Departments of Community and Environmental Medicine [R. C. S.] and Pharmacology [R. A. B.], College of Medicine, University of California, Irvine, and University of California Southern Occupational Health Center [R. C. S.], Irvine, California 92717

The kinetics of formation and persistence of 7-ethylguanine (e⁷Gua) and O⁶-ethylguanine (O⁶eGua) were determined in rat liver and kidney DNA following i.p. injection with 12.5, 50, 100, or 200 mg DENA per kg body weight. The rate of ethylguanine formation in hepatic DNA was independent of carcinogen dose; however, the maximum level of DNA ethylation reached was linearly related to DENA dose. Persistence of O⁶eGua but not e⁷Gua in rat liver DNA appeared to be dose-dependent; the rate of decline in O⁶eGua concentration slowed as the dose of DENA increased. Ethylation of rat kidney DNA was quantifiable only following treatment with 200 mg DENA per kg body weight, and maximum concentrations of e⁷Gua and O⁶eGua were approximately ten times less than those in hepatic DNA of these animals. Nevertheless, elimination of e⁷Gua and O⁶eGua from DNA occurred at similar rates in these tissues. Whereas lung DNA from DENA-treated rats contained no detectable ethylguanines, both e⁷Gua and O⁶eGua were detected in lung DNA from treated hamsters. The half-life of e⁷Gua in hamster lung DNA was 28 h, while O⁶eGua persisted longer, exhibiting a half-life of 91 h. Only trace quantities of e⁷Gua and O⁶eGua were detected in hamster kidney DNA, precluding an accurate estimation of the kinetics of DNA alkylation in this tissue. The rate of formation of ethylguanines in hepatic DNA was faster in hamster than in rat, while maximum levels of e⁷Gua and O⁶eGua were similar in these two species. Persistence of both e⁷Gua and O⁶eGua was markedly different in hepatic DNA of rats and hamsters. e⁷Gua was eliminated at a faster rate in the hamster (half-life of 20 h), as compared to the rat (half-life of 35 h). Conversely, O⁶eGua persisted longer in hamster than in rat liver DNA; a half-life of 34 h was found for the hamster, compared to a half-life of 14 h for the rat. The half-lives of e⁷Gua and O⁶eGua in hepatic DNA of DENA-treated rats and hamsters were similar to those reported previously for m⁷Gua and O⁶mGua in these species, suggesting that the same enzymatic DNA repair systems act upon these structurally related DNA adducts. The formation and prolonged persistence of O⁶eGua in lung DNA of DENA-treated hamsters may be related to the sensitivity of this species to the induction of respiratory tract neoplasms following exposure to DENA.

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 F33615-80-C0512 from the United States Air Force.

² Present address: Division of Environmental Carcinogenesis, International Agency for Research on Cancer, 150 cours Albert-Thomas, 69372 Lyon, France.

³ To whom requests for reprints should be addressed.

Received 9/ 4/84. Revised 1/14/85. Accepted 1/31/85.