Lack of modification of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) rat hepatocarcinogenesis by caffeine, a CYP1A2 inducer, points to complex counteracting influences.
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), one of the most abundant carcinogenic heterocyclic amines in cooked foods, is speculated to be a human liver carcinogen. To test the hypothesis that it is metabolically activated by CYP1A2, we here investigated the effects of caffeine as a CYP1A2 inducer on MeIQx induced rat hepatocarcinogenesis in a medium-term liver bioassay system. Unexpectedly, no modifying effects of caffeine on MeIQx-induced hepatocarcinogenesis were evident, although up-regulation of CYP1A2 and NAT2 were detected. Therefore, mRNAs extracted from GST-P positive foci and the surrounding liver tissue in each group were analyzed to explore mechanisms in detail. The results suggest that suppression of syndecan-2 (Sdc2) and induction of cell cycle arrest through a p21-dependent pathway might have counter-acted any promotion effects of up-regulation of CYP1A2.
Kuribayashi
Masanori
M
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. kuribayashi@ono.co.jp
Asamoto
Makoto
M
Suzuki
Shugo
S
Hokaiwado
Naomi
N
Ogawa
Kumiko
K
Shirai
Tomoyuki
T
D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002273:Carcinogens / Q000633:toxicity*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D003580:Cytochromes; D004790:Enzyme Induction; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011509:Proteoglycans / Q000235:genetics; D011810:Quinoxalines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D053669:Syndecan-2
D002273:Carcinogens; D003580:Cytochromes; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D011810:Quinoxalines; C508245:SDC2 protein, human; C508247:Sdc2 protein, rat; D053669:Syndecan-2; D002110:Caffeine; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D000123:Acetyltransferases