The mutagenic response at the ouabain resistance locus in T cells of mice exposed to N-ethyl-N-nitrosourea parallels the response at the Hprt locus and correlates with mutation target size

The lymphocyte Hprt gene has been used extensively as a reporter locus tomonitor the mutational effects of the exposure of animals to genotoxicants.Implicit in this view of the function of a reporter gene is the assumptionthat its mutagenic response is representative of that of other genes in theorganism. As a test of this hypothesis we compared the frequency of6-thioguanine-resistant (TGr) mutants at the Hprt locus with the mutantfrequency (MF) induced at another locus, the ouabain resistance (Oua)locus. The frequency of spontaneous OUA(R) mutants was estimated to be1.1x10(-7) (MF between <0.3 and 1.1x10(- 7)), which was approximately30-fold less than the spontaneous TGr MF. Following treatment withN-ethyl-N-nitrosourea (ENU), the induced OUA(R) MF at each of two doselevels (50 and 150 mg/kg ENU) and two time points (3 and 6 weekspost-exposure) was consistently 8- to 9-fold lower than the correspondingTGr MF. Thus the mutagenic response of the Oua locus closely paralleledthat of the Hprt locus, indicating a similarity in their response to ENU.In addition, the Oua locus was 3-4 times more sensitive than the Hprt locusto the mutagenic effect of ENU, as measured by the fold increase in MF overthe background level. The number of ENU-mutable sites capable of resultingin a TGr or OUA(R) phenotype, otherwise known as the mutation target size,was estimated to differ by an order of magnitude between the two loci. Thisdifference in target size correlates with, and therefore may largelyaccount for, the difference in induced MF between both loci.