Effect of chronic ethanol diet on the replication, alkylation, and repair of DNA from hepatocytes and nonparenchymal cells following dimethylnitrosamine administration.
Chronic alcohol ingestion has been associated with human cancer of the larynx, esophagus, and liver, however the mechanism(s) of ethanol's interaction in either initiation and/or progression of cancer is unknown. The initiation of chemical carcinogenesis is thought to involve an alteration of the DNA which becomes fixed in the daughter strand following the replication of DNA containing promutagenic damage. The purpose of this study was to investigate the effects of a chronic ethanol diet and acute dimethylnitrosamine administration on the replication, alkylation, and repair of DNA from nonparenchymal cells and hepatocytes of rat liver. DNA replication of nonparenchymal cells, but not hepatocytes, was inhibited in animals on the chronic ethanol diet. Dimethylnitrosamine exposure reversed this inhibitory effect 24 h after exposure. Hepatocyte alkylation and repair of DNA following dimethylnitrosamine administration was unaffected by the ethanol diet. 7-Methylguanine was lost from both cell populations equally during a 72 h time course. In contrast, O6-methylguanine was removed much more efficiently in hepatocytes. The nonparenchymal cells had 10 times more O6-methylguanine than hepatocytes 72 h after dimethylnitrosamine administration. Lower concentrations of 7-methylguanine and O6-methylguanine were present in nonparenchymal cells of ethanol treated rats compared to controls. Although in vitro studies have demonstrated increased microsomal activation and mutagenesis of dimethylnitrosamine following chronic ethanol ingestion, the present study demonstrates that in vivo metabolism of dimethylnitrosamine resulting in DNA alkylation is not increased by chronic ethanol exposure.
D000478:Alkylation; D000818:Animals; D002469:Cell Separation; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D004128:Dimethylnitrosamine / Q000633:toxicity*; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344
D000431:Ethanol; D006147:Guanine; C008450:7-methylguanine; D004247:DNA; C008449:O-(6)-methylguanine; D004128:Dimethylnitrosamine