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Marked Differences in the Role of O⁶-Alkylguanine in hprt Mutagenesis in T-Lymphocytes of Rats Exposed in Vivo to Ethylmethanesulfonate, N-(2-Hydroxyethyl)-N-nitrosourea, or N-Ethyl-N-nitrosourea¹

MGC-Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, Wassenaarseweg 72, 2333 AL Leiden [J. G. J., H. V., C. M. M. v. T., G. R. M., A. D. T., A. A. v. Z.]; Laboratory of Carcinogenesis and Mutagenesis, National Institute of Public Health and Environmental Protection, Bilthoven [G. R. M.]; and J. A. Cohen Institute, Interuniversity Research Institute for Radiopathology and Radiation Protection, Leiden [H. V., A. A. v. Z.], the Netherlands

The role of DNA alkylation at the O⁶ position of guanine in the induction of gene mutations in vivo was studied in the hprt gene of rat T-lymphocytes from spleen exposed in vivo to the monofunctional ethylating agents ethylmethanesulfonate (EMS) and N-ethyl-N-nitrosourea (ENU), or the hydroxyethylating agent N-(2-hydroxyethyl)-N-nitrosourea (HOENU). All chemicals showed an exposure-dependent increase in hprt mutant frequency. HOENU and ENU, however, were much more mutagenic than EMS when compared at equimolar levels. DNA sequence analysis was performed on PCR products of hprt cDNA from 40 EMS-, 35 HOENU-, and 46 ENU-induced 6-thioguanine-resistant T-lymphocyte clones. Thirty EMS-induced mutants contained a single base pair substitution with GC to AT transitions being the predominant type of mutation (26 of 30) which are probably caused by mispairing of O⁶-ethylguanine with T during DNA replication. No strand specificity of mutated G's among GC to AT transitions was observed. Twenty-three HOENU- and 42 ENU-induced mutants contained a single base pair substitution. In contrast to EMS, GC to AT transitions were found at a low frequency, 4 of 23 for HOENU and 5 of 42 for ENU, indicating that O⁶-hydroxyethylguanine and O⁶-ethylguanine are less important in HOENU- and ENU-induced mutagenesis in vivo, respectively. Also here no strand bias for mutated G's was observed, although the number of this type of mutation was limited. The most frequently induced base pair alterations by HOENU and ENU were transversions at AT base pairs, 16 of 23 and 28 of 42, respectively, with AT to TA being the predominant type of mutation. In both ENU and HOENU mutational spectra, an extreme strand bias for mutated T's toward the nontranscribed strand was found. The results suggest that DNA damage induced in rat T-lymphocytes in vivo by HOENU and ENU is processed in similar ways.

¹ Parts of these studies were supported by a grant from the Commission of the European Communities Environmental Programme (Contract EV5V-CT93-0246).

² To whom requests for reprints should be addressed.

Received 11/29/94. Accepted 2/24/95.

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