Carcinogenesis, Vol 18, 1555-1560, Copyright © 1997 by Oxford University Press
H Frandsen
The heterocyclic aromatic amines, 2-amino-1-methyl-6-phenylimidazo[4,5-
b]pyridine (PhIP) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline
(4,8-DiMeIQx) are formed during frying of meat. PhIP and 4,8-DiMeIQx have,
after metabolic activation, been shown to form adducts with DNA at the C8
of guanine both in vitro and in vivo. In order to investigate possible
urinary biomarkers for estimation of the genotoxic dose of PhIP and
4,8-DiMeIQx, [3H]PhIP-dG, [3H]PhIP-DNA and [14C]4,8-DiMeIQx- DNA were
injected i.p. to rats and the excretion of radioactivity in urine and
faeces were measured. For all three [3H]PhIP-dG, [3H]PhIP-DNA and
[14C]4,8-DiMeIQx-DNA 15-20% of the dose were excreted in the urine and
80-85% of the dose were excreted in the faeces. Urinary excretion showed
maximum to 24 h (90%) with a rapid decline, 10% to 48 h and 0% to 72 h.
Faecal excretion also showed maximum to 24 h (60%) with a slower decline,
30% to 48 h and 10% to 72 h. HPLC analysis of samples of urine and extracts
from faeces, from rats dosed with [3H]PhIP-dG, showed that approximately
90% of the radioactivity co-eluted with PhIP- dG, indicating that PhIP-dG
is excreted unmetabolized. HPLC analysis of samples of urine and extracts
from faeces, from rats dosed with [3H]PhIP-DNA, showed that approximately
85% of the radioactivity co- eluted with PhIP-dG, indicating that PhIP-DNA
adducts is mainly excreted as nucleoside adducts. Approximately 5% of the
radioactivity excreted in the urine co-eluted with PhIP-G, indicating loss
of deoxyribose. HPLC analysis of samples of urine and extracts from faeces,
from rats dosed with [14C]4,8-DiMeIQx-DNA, showed that approximately 90% of
the radioactivity co-eluted with 4,8-DiMeIQx-dG, indicating that
4,8-DiMeIQx-DNA adducts is mainly excreted as nucleoside adducts. Man is
able to eliminate compounds of a higher mol. wt in the urine than the rat,
the percentage of PhIP-dG and 4,8-DiMeIQx eliminated in the urine of man
would therefore be expected to be higher than in the rat. Measurement of
urinary nucleoside adducts of PhIP and 4,8-DiMeIQx could therefore provide
a basis for the development of a biomonitoring strategy for the genotoxic
dose of these food derived HAA.
ARTICLES
Excretion of DNA adducts of 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, PhIP- dG, PhIP-DNA and DiMeIQx-DNA from the rat
Institute of Toxicology, National Food Agency, Soborg, Denmark.
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