Ability of N-methyl-N'-nitro-N-nitrosoguanidine, 4-nitroquinoline 1-oxide, dimethylnitrosamine, and NaCl to induce unscheduled DNA synthesis, stimulate replicative DNA synthesis, and produce DNA single-strand breaks in pyloric mucosa of rat stomach.
Male F344 rats were given test chemicals orally, and samples of their pyloric mucosa were incubated in vitro. Induction of unscheduled DNA synthesis (UDS) and stimulation of replicative DNA synthesis in the pyloric mucosa were then examined by addition of [3H]thymidine and simultaneous determinations of DNA synthesis in the presence and absence of hydroxyurea, an inhibitor of replicative DNA synthesis. DNA damage was also examined by the alkaline elution method with DNA single-strand scission as a marker. The results showed four types of abilities of the chemicals to affect UDS and replicative DNA synthesis in the pyloric mucosa of rat stomach 1-2 h after their administration: (1) induction of UDS and stimulation of replicative DNA synthesis by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a glandular stomach carcinogen, (2) induction of only UDS by 4-nitroquinoline 1-oxide (4NQO), a glandular stomach carcinogen, (3) stimulation of only replicative DNA synthesis by NaCl, a glandular stomach tumor promoter, and (4) neither induction of UDS nor stimulation of replicative DNA synthesis by dimethylnitrosamine (DMN), a liver carcinogen. DNA single-strand scission was induced by MNNG and 4NQO, being maximal 2 h after their administration, but was not induced by NaCl or DMN. Thus it correlated well with the induction of UDS. The present results indicate four types of inductive abilities of chemicals on UDS and replicative DNA synthesis in rat stomach pyloric mucosa and show that this method can detect differences in the action mechanisms and organ specificities of glandular stomach carcinogens.
Ohsawa
K
K
Department of Molecular Oncology, University of Tokyo, Japan.
Furihata
C
C
Mori
M
M
Ikui
E
E
D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000633:toxicity; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D011708:Pylorus; D051381:Rats; D011916:Rats, Inbred F344; D012965:Sodium Chloride / Q000633:toxicity*
D002273:Carcinogens; D004277:DNA, Single-Stranded; D008769:Methylnitronitrosoguanidine; D012965:Sodium Chloride; D015112:4-Nitroquinoline-1-oxide; D004247:DNA; D004128:Dimethylnitrosamine