Synergistic enhancement of glutathione S-transferase placental form-positive hepatic foci development in diethylnitrosamine-treated rats by combined administration of five heterocyclic amines at low doses.
Potential synergism among 5 heterocyclic amines at low doses in the induction of glutathione S-transferase placental form (GST-P)-positive liver cell foci was examined in an 8-week experiment using male rats initially given diethylnitrosamine (200 mg/kg, ip). The heterocyclic amines applied were 3-amino-1-methyl-5H-pyrido[4,3-b]indole (500 ppm), 2-amino-6-methyldipyrido[1,2-a:3',2'-d]-imidazole (500 ppm), 2-amino-3-methyl-9H-pyrido[2,3-b]indole (800 ppm), 2-amino-9H-pyrido[2,3-b]indole (800 ppm), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP, 400 ppm). Separate groups received each chemical at the dose used in earlier carcinogenicity assays (above doses), at 1/5 or 1/25 of these, or all 5 chemicals together, each at the 1/5 or 1/25 levels. The numbers and areas of GST-P-positive foci were significantly increased with all chemicals, except for PhIP, at the highest dose, the results being consistent with the reported liver carcinogenicity. In the combined treatment at the 1/5 dose levels, synergistic enhancement occurred; the numbers and areas of foci were significantly increased above the sums of individual data. However, this was not the case for the 1/25 dose groups. Although the synergism between pyrolysis products in liver carcinogenesis depended on the dose and combination of chemicals, the findings, together with those from a previous experiment using 5 different heterocyclic amines, are of particular significance since several heterocyclic amines might be simultaneously generated during cooking of foodstuffs.
Hasegawa
R
R
First Department of Pathology, Nagoya City University Medical School.
Shirai
T
T
Hakoi
K
K
Takaba
K
K
Iwasaki
S
S
Hoshiya
T
T
Ito
N
N
Nagao
M
M
Sugimura
T
T
D000588:Amines / Q000009:adverse effects*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests / Q000379:methods; D002274:Carcinogens, Environmental / Q000009:adverse effects; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis*; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010920:Placenta / Q000201:enzymology; D051381:Rats; D011916:Rats, Inbred F344
D000588:Amines; D002274:Carcinogens, Environmental; D004052:Diethylnitrosamine; D005982:Glutathione Transferase