Carcinogenesis, Vol 19, 1749-1754, Copyright © 1998 by Oxford University Press
PM Leong-Morgenthaler, C Op Het Velt, E Jaccaud and RJ Turesky
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ), a heterocyclic aromatic amine
that has been identified in cooked meats and cigarette condensates, is
mutagenic in human lymphoblastoid TK6 cells at the thymidine kinase and
hypoxanthine-guanine phosphoribosyl transferase (hprt) loci. Treatment of
the cells with IQ following activation with either an exogenous
metabolizing mixture (S9) or following photoactivation of the
azido-derivative of IQ (N3-IQ) showed that the photolytic-derivative of
N3-IQ was more active. This observation is consistent with other reports
that indicate that the weak mutagenicity of IQ in mammalian cells is caused
by the lack of enzymes required for the ultimate activation of the compound
within the cells. Two DNA adducts were found by 32P-post-labelling in the
cells treated with the photoactivated N3-IQ. The major adduct was
identified as N-
(deoxyguanosin-8-yl)-2-amino-3-methylimidazo[4,5-f]quinoline (dG-C8-IQ) and
the minor adduct as 5-(deoxyguanosin-N2-yl)-2-amino-3-
methylimidazo[4,5-f]quinoline (dG-N2-IQ). The ratio of the dG-C8IQ to the
dG-N2-IQ adducts was approximately 3:1 and did not significantly change in
cultures treated with different concentrations of the mutagen.
Approximately 50% of the adducts were removed 9 h after treatment with IQ
and <10% of these adducts remained after 24 h. There was no significant
preferential repair of either adduct under the experimental conditions
used. The identification of 15 mutations induced at the hprt locus (of the
44 mutants analysed) showed IQ to be efficient at inducing single base
deletions in a run of guanines. Six single guanine deletions were observed
in the run of six guanines in exon III and one deletion of a single guanine
was observed in a non- repetitive sequence in exon VI. Other mutations
observed were two GC-- >TA transversions, two GC-->CG transversions,
one AT-->TA transversion and one GC-->AT transition. In addition, two
multiple mutations were found. The majority of the identified mutations
(12/15) occurred at GC base pairs and suggests either the dG-C8-IQ or the
dG-N2-IQ adduct to be the pre-mutagenic lesion.
ARTICLES
Mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in human lymphoblastoid cells
Institute of Pharmacology and Toxicology, University of Lausanne, Switzerland. phaikmooi.morgenthaler-leong@ipharm.unil.ch
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