DNA methylation in rat stomach and duodenum following chronic exposure to N-methyl-N'-nitro-N-nitrosoguanidine and the effect of dietary taurocholate.
N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces a high incidence of carcinomas in the glandular stomach of rats following chronic administration in the drinking water. We determined the level of 7-methylguanine and O6-methylguanine in gastric and duodenal DNA during chronic exposure to MNNG (80 p.p.m.). After considerable fluctuations during the initial 3 weeks, levels of methylpurines reached a steady state which was approximately three times higher in the pylorus (i.e. the preferential site of tumor induction) than in the fundus and duodenum, with 7-methylguanine and O6-methylguanine values in the range of 520 and 110 mumol/mol guanine, respectively. When rats were given MNNG in the drinking water at concentrations ranging from 10 to 80 p.p.m. for 3 weeks, levels of methylpurines reached maximum values already at 10-20 p.p.m. At higher MNNG concentrations, there was no further increase in DNA alkylation. The reason for this lack of dose response remained unclear. Immunohistochemical analyses showed that DNA methylation by MNNG is restricted to epithelial cells bordering the luminal surface. The possibility exists that in this target cell population the content of free thiols is a limiting factor for the decomposition of MNNG and its reaction with macromolecules in the gastric mucosa. Addition to the diet of sodium taurocholate, a bile acid previously shown to enhance MNNG-induced stomach carcinogenesis, did not influence the extent of DNA methylation, indicating that it acts as a promoter.
Kobori
O
O
1st Department of Surgery, Faculty of Medicine, University of Tokyo, Japan.
Schmerold
I
I
Ludeke
B
B
Ohgaki
H
H
Kleihues
P
P
D000818:Animals; D004247:DNA / Q000378:metabolism*; D004032:Diet; D004386:Duodenum / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D008297:Male; D008745:Methylation; D008769:Methylnitronitrosoguanidine / Q000378:metabolism*; D009928:Organ Specificity; D051381:Rats; D011919:Rats, Inbred Strains; D013274:Stomach Neoplasms / Q000139:chemically induced; D013656:Taurocholic Acid / Q000494:pharmacology*
D008769:Methylnitronitrosoguanidine; D013656:Taurocholic Acid; D004247:DNA