Carcinogenesis, Vol 19, 755-764, Copyright © 1998 by Oxford University Press
KL Dobo, DA Eastmond and AJ Grosovsky
N-Nitrosodimethylamine (NDMA) is a potent mutagen and animal carcinogen to
which many people are exposed through the consumption of contaminated food
and the use of tobacco products. Although the mutational specificity of
NDMA has been studied in bacteria, little is known about the specific types
of mutations induced by NDMA in the human genome. Knowledge of the
mutational spectrum of NDMA in human genes may help to substantiate the
role of NDMA in the etiology of human cancers. In the current study, the
mutational spectrum of NDMA was characterized at the tk and hprt loci, in
human lymphoblastoid cells capable of metabolically activating NDMA. A
number of patterns were observed among NDMA-induced mutations. At both
marker loci, G:C-- >A:T transitions dominated the mutational spectrum of
NDMA, which were indicative of the mutagenicity of the O6meG lesion. In
addition, the majority of G:C-->A:T mutations occurred at guanines 3' to
another guanine. Almost all of these mutations originated on the non-
transcribed strand, which suggests that transcription-coupled repair
influenced the distribution of G:C-->A:T transitions at the tk and hprt
loci. Furthermore, the observation of hotspots for G:C-->A:T mutations,
within both loci, suggests that differential repair kinetics may exist, and
consequently affect the distribution of mutations. Finally, a comparison of
the site specificity of G:C-->A:T mutations at the tk and hprt loci,
indicated that the gene used for mutational analysis influenced the site
specificity of NDMA-induced mutations, and possibly reflects the number of
5'-GG-3' sites in the tk and hprt loci that when mutated would yield a
mutant phenotype.
ARTICLES
Sequence specific mutations induced by N-nitrosodimethylamine at two marker loci in metabolically competent human lymphoblastoid cells
Environmental Toxicology Graduate Program, University of California, Riverside 92521, USA.
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