Enhancement of rat liver cell foci development by combined treatment with heterocyclic amines at low doses.
Potential synergism between 5 or 10 carcinogenic heterocyclic amines (Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2, IQ, MeIQ, MeIQx, MeA alpha C, A alpha C and PhIP) acting at low doses was examined in a medium-term liver bioassay system for carcinogens. Immunohistochemically-demonstrated glutathione S-transferase placental form (GST-P) positive foci were assessed as the endpoint marker lesions. Male F344 rats were initially given diethylnitrosamine (DEN, 200mg/kg, ip) and beginning 2 weeks later received heterocyclic amines individually or in combination for 6 weeks. All animals were subjected to partial hepatectomy at week 3 and killed at week 8. A clear dose response relationship was observed for all heterocyclic amines, except for the nonhepatocarcinogen PhIP, with the dose used in earlier carcinogenicity assays and 1/5, 1/10, 1/25 and 1/100 of these levels. Carcinogenicity could be predicted for all compounds at the highest dose or lower dose levels except for PhIP. With combined administration of 5 or 10 chemicals, foci induction significantly exceeded the sums of 5 or 10 individual data for the 1/5, 1/10 and 1/25 dose levels, but not for the 1/100 case. The findings are of particular significance since several heterocyclic amines and other carcinogenic agents might be simultaneously generated during cooking, although each at very low concentration.
Ito
N
N
First Department of Pathology, Nagoya City University Medical School, Japan.
Hasegawa
R
R
Asakawa
E
E
Hirose
M
M
Imaida
K
K
Hagiwara
A
A
D000588:Amines / Q000633:toxicity*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005982:Glutathione Transferase / Q000032:analysis*; D006571:Heterocyclic Compounds / Q000633:toxicity*; D007527:Isoenzymes / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D000588:Amines; D014408:Biomarkers, Tumor; D002273:Carcinogens; D006571:Heterocyclic Compounds; D007527:Isoenzymes; D004052:Diethylnitrosamine; D005982:Glutathione Transferase