Differential susceptibility of rat and guinea pig colon mucosa DNA to methylation by methylazoxymethyl acetate in vivo.
Methylazoxymethanol (MAM) and methylazoxymethyl acetate (MAMOAc) are powerful colon carcinogens in rats, mice and hamsters. In contrast, these agents are not carcinogenic to the colon of the guinea pig. To probe the mechanism responsible for this species difference, we determined the levels of DNA methylation in the livers and colon mucosae of F344 rats and strain-2 guinea pigs after the s.c. administration of 25 mg/kg MAMOAc. While no significant difference was observed between the two species with respect to the degree of liver DNA methylation, the level of O6-methylguanine in guinea pig colon mucosa DNA was 19 times lower than in rat colon mucosa DNA, and the level of 7-methylguanine was below detection limits. However, significant colon mucosa DNA methylation was observed in the guinea pig after the intrarectal administration of 1.25 mg methylnitrosourea. The methylation of colon mucosa DNA in response to MAMOAc in the two species correlated with the activity of alcohol dehydrogenase, an enzyme believed to be involved in the activation of MAM. Thus the resistance of the guinea pig colon to the carcinogenicity of MAM/MAMOAc may be ascribed to the lack of metabolic activation of MAM in this organ.
Sohn
O S
OS
Puz
C
C
Caswell
N
N
Fiala
E S
ES
D000426:Alcohol Dehydrogenase; D000429:Alcohol Oxidoreductases / Q000032:analysis; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D006168:Guinea Pigs; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008745:Methylation; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D001391:Azo Compounds; D008746:Methylazoxymethanol Acetate; D004247:DNA; D000429:Alcohol Oxidoreductases; D000426:Alcohol Dehydrogenase; C030667:methylazoxymethanol