Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses.
Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.
Ito
N
N
First Department of Pathology, Nagoya City University Medical School, Japan.
Hasegawa
R
R
Shirai
T
T
Fukushima
S
S
Hakoi
K
K
Takaba
K
K
Iwasaki
S
S
Wakabayashi
K
K
Nagao
M
M
Sugimura
T
T
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002243:Carbolines / Q000633:toxicity; D002273:Carcinogens; D004357:Drug Synergism; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism*; D007093:Imidazoles / Q000633:toxicity; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008113:Liver Neoplasms / Q000139:chemically induced*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011804:Quinolines / Q000633:toxicity; D011810:Quinoxalines / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D002243:Carbolines; D002273:Carcinogens; D007093:Imidazoles; D011804:Quinolines; D011810:Quinoxalines; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D005982:Glutathione Transferase; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole; C023847:Glu-P-2