2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-induced hepatocarcinogenesis is not enhanced by CYP1A inducers, alpha- and beta-naphthoflavone: relationship to intralobular distribution of CYP1A expression.
Interaction of more than two chemicals from foods is a very important factor for carcinogenic risk assessment and management. 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. MeIQx is metabolically activated by CYP1A2 and then N-acetyltransferase (NAT), findings that suggest that its carcinogenic potential might be enhanced by simultaneous exposure to chemical(s) inducing CYP1A2. Therefore, we here investigated the effects of alpha- and beta-naphthoflavone as CYP1A2 inducers on MeIQx-induced rat hepatocarcinogenesis in a medium-term rat liver bioassay. Unexpectedly, no modifying influence of naphthoflavones on MeIQx-induced hepatocarcinogenesis was demonstrated with reference to glutathione S-transferase placental form (GST-P) positive foci in the liver, although up-regulation of CYP1A2 was detected on Western blot analysis. Activity of NAT was not affected. In MeIQx-treated rats, CYP1A expression was mainly detected in zone 3 of the liver where GST-P positive foci were preferentially located, while naphthoflavones alone or combinations of naphthoflavones and MeIQx induced CYP1A expression in zone 1. This difference in intralobular distribution of CYP1A might be related to the fact that MeIQx hepatocarcinogenesis was not modified by the two CYP1A inducers.
Suzuki
Shugo
S
Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan. shugo@med.nagoya-cu.ac.jp
Takeshita
Kentaro
K
Doi
Yuko
Y
Asamoto
Makoto
M
Takahashi
Satoru
S
Naiki-Ito
Aya
A
Shirai
Tomoyuki
T
D000704:Analysis of Variance; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D001571:Benzoflavones / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2; D003580:Cytochromes / Q000096:biosynthesis*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D011810:Quinoxalines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D019324:beta-Naphthoflavone / Q000633:toxicity*
D001571:Benzoflavones; D003580:Cytochromes; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011810:Quinoxalines; C011512:alpha-naphthoflavone; D019324:beta-Naphthoflavone; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C017170:Cyp1a2 protein, rat; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C541077:NAT2 protein, rat