Carcinogenesis, Vol 18, 2233-2237, Copyright © 1997 by Oxford University Press
SB Dass, RH Heflich and DA Casciano
The lymphocyte Hprt gene has been used extensively as a reporter locus to
monitor the mutational effects of the exposure of animals to genotoxicants.
Implicit in this view of the function of a reporter gene is the assumption
that its mutagenic response is representative of that of other genes in the
organism. As a test of this hypothesis we compared the frequency of
6-thioguanine-resistant (TGr) mutants at the Hprt locus with the mutant
frequency (MF) induced at another locus, the ouabain resistance (Oua)
locus. The frequency of spontaneous OUA(R) mutants was estimated to be
1.1x10(-7) (MF between <0.3 and 1.1x10(- 7)), which was approximately
30-fold less than the spontaneous TGr MF. Following treatment with
N-ethyl-N-nitrosourea (ENU), the induced OUA(R) MF at each of two dose
levels (50 and 150 mg/kg ENU) and two time points (3 and 6 weeks
post-exposure) was consistently 8- to 9-fold lower than the corresponding
TGr MF. Thus the mutagenic response of the Oua locus closely paralleled
that 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 locus
to the mutagenic effect of ENU, as measured by the fold increase in MF over
the background level. The number of ENU-mutable sites capable of resulting
in 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. This
difference in target size correlates with, and therefore may largely
account for, the difference in induced MF between both loci.
ARTICLES
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
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
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