In order to elucidate whether mixed exposure to environmental carcinogens a
nd caffeine increases the risk of cancer induction, we investigated the rel
ationship between preneoplastic lesion development in the liver and colon a
nd drug metabolizing enzyme induction and DNA adduct formation, in rats tre
ated with a mixture of heterocyclic amines (HCAs) and caffeine. In Experime
nt I, male F344 rats were administered 3 different HCAs, the food carcinoge
ns, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimida
zo[4,5-f]quinoxaline (MeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]py
ridine (PhIP), alone or in combinations of 2 or 3 at 50 ppm in the diet for
16 weeks. The numbers of hepatic glutathione-S-transferase P form positive
(GST-P+) foci and colonic aberrant crypt foci (ACF) were greater in the IQ
+ MeIQx group than expected from simple summation and increased levels of
HCA-DNA adducts were noted. However, no summation was obtained when combine
d with PhIP, which rather caused inhibition. In Experiment 2, the effects o
f concurrent caffeine administration on the PhIP carcinogenicity were asses
sed. Caffeine at 1000 and 500 ppm in the drinking water for 2 weeks signifi
cantly increased levels of CYP1A2. Ten weeks concurrent administration of c
affeine (1000 ppm) and PhIP (400 ppm) resulted in significant increase of c
olon ACFs and CYP1A2 expression. Thus, concurrent administration of IQ and
MeIQx caused elevation of their carcinogenicity but other mixtures with PhI
P did not enhance carcinogenicity. However, a noncarcinogen, caffeine, enha
nced PhIP colon carcinogenesis, possibly due to induction of CYP1A2. (C) 19
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