Enhanced repair of O6-methylguanine in liver DNA of rats pretreated with phenobarbital, 2,3,7,8-tetrachlorodibenzo-p-dioxin, ethionine, or N-alkyl-N-nitrosoureas.
Rats were pretreated for a number of weeks with the liver tumour promoters phenobarbital and 2,3,7,8-tetrachlorodibenzo-p-dioxin, the direct alkylating agents N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea, and the hepatocarcinogens ethionine and diethylnitrosamine. A subsequent challenge with a single, low dose of radioactively labelled dimethylnitrosamine was given to assay the capacity of the liver for O6-methylguanine repair. Pretreatment with 0.05% phenobarbital in the diet for 8 weeks (a promoting regimen) resulted in significantly enhanced O6-methylguanine repair; shorter pretreatment periods (3 days or 2 weeks) had no significant effect. Repeated injection of another liver tumour promoter, 2,3,7,8-tetrachlorodibenzo-p-dioxin, also resulted in enhancement of O6-methylguanine repair. Pretreatment for 2 weeks with N-ethyl-N-nitrosourea resulted in strongly enhanced O6-methylguanine repair, as did a similar pretreatment with diethylnitrosamine, which was included as a positive control. The same pretreatment scheme which was highly effective in the case of N-ethyl-N-nitrosourea, was found to be totally ineffective in the case of N-methyl-N-nitrosourea. When N-methyl-N-nitrosourea was administered for 8 weeks instead of 2, a small but statistically significant increase in O6-methylguanine repair was observed. It is concluded that two factors are responsible for the low effectivity of N-methyl-N-nitrosourea. The first is the relatively low extent of liver DNA methylation by this compound when compared with dimethylnitrosamine. The second is the low efficiency of methylating agents (expressed per extent of DNA alkylation) to induce O6-methylguanine repair in rat liver when compared with ethylating agents. Pretreatment for 2 weeks with a diet containing DL-ethionine also resulted in a substantially increased O6-methylguanine repair capacity. Neither this enhancement, nor that induced by a pretreatment with diethylnitrosamine, could be inhibited by simultaneous feeding of a methionine-enriched diet. Our results indicate that neither increased hepatocellular proliferation nor direct interaction with DNA are necessary for the induction of O6-methylguanine repair enhancement. It is concluded that the capacity of an agent to enhance O6-methylguanine repair in rat liver reflects the hepato(co)carcinogenic capacity of that agent.
D000478:Alkylation; D000818:Animals; D004247:DNA / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D004147:Dioxins / Q000494:pharmacology*; D005001:Ethionine / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000494:pharmacology; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D010634:Phenobarbital / Q000494:pharmacology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D004147:Dioxins; D009607:Nitrosourea Compounds; D000072317:Polychlorinated Dibenzodioxins; D006147:Guanine; D004247:DNA; C008449:O-(6)-methylguanine; D008715:Methionine; D005001:Ethionine; D010634:Phenobarbital