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 tumourpromoters phenobarbital and 2, 3, 7, 8-tetrachlorodi-benzo-p-dioxin,the direct alkylating agents N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea,and the hepatocardnogens ethionine and diethylnitrosamine. Asubsequent challenge with a single, low dose of radioactivelylabelled dimethyl-nitrosamine was given to assay the capacityof the liver for O⁶-methylguanine repair. Pretreatment with0.05% 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 significanteffect. Repeated injection of another liver tumour promoter,2,3, 7, 8-tetrachlorodibenzo-/>-dioxin, also resulted inenhancement of O⁶methylguanine repair. Pretreatment for 2 weekswith N-ethyl-N‘-nitrosourea resulted in strongly enhancedO6-methylguanine repair, as did a similar pretreatment withdiethylnitrosamine, which was included as a positive control.The same pretreatment scheme which was highly effective in thecase of N’-ethyl-N-nitrosoiirea, was found to be totallyin effective in the case of N-methyl-N-nitrosourea. When N methyl-N-nitrosoureawas administered for 8 weeks instead of 2, a small but statisticallysignificant increase in O⁶-methyl-guanine repair was observed.It is concluded that two factors are responsible for the loweffectivity of N-methyl-N-nitroso-urea. The first is the relativelylow extent of liver DNA methylation by this compound when comparedwith dimethyl-nitrosamine. The second is the low efficiencyof methylating agents (expressed per extent of DNA alkylation)to induce O⁶-methylguanine repair in rat liver when comparedwith ethylating agents. Pretreatment for 2 weeks with a dietcontaining DL-ethionine also resulted in a substantially increasedO⁶-methylguanine repair capacity. Neither this enhancement,nor that induced by a pretreatment with diethylnitrosamine,could be inhibited by simultaneous feeding of a methionine-enricheddiet. Our results indicate that neither increased hepatocellularproliferation nor direct interaction with DNA are necessaryfor the induction of O⁶-methylguanine repair enhancement. Itis concluded that the capacity of an agent to enhance O⁶-methylguaninerepair in rat liver reflects the hepato(co)carcinogenic capacityof that agent.