Ethanol modulates rat hepatic DNA repair functions.
To further explore how ethanol may act at the DNA level, studies have been made of DNA repair mechanisms in male Wistar rats given ethanol either as an acute intragastric dose (5 g/kg) or continuously in a liquid diet (5% w/v) to provide 36% of the caloric intake. These treatments generate significant levels of free radicals with evidence of damage to DNA. The acute ethanol dose significantly inhibited O(6)-alkylguanine-DNA alkyltransferase (ATase) activity by 21-32% throughout the 24-h post-treatment period and this was confirmed by immunohistochemical detection of the ATase protein in hepatic nuclei. Twelve hours after the ethanol treatment, the activities of the DNA glycosylases, alkylpurine-DNA-N-glycosylase (APNG) and 8-oxoguanine-DNA glycosylase (OXOG glycosylase) were each increased by approximately 44%. In contrast, when given chronically via the liquid diet, ethanol initially had no effect on ATase activity, but after 4 weeks ATase activity was increased by 40%. Following ethanol withdrawal, ATase activity remained elevated for at least 12 h, but, by 24 h, the activity had fallen to the uninduced control level. DNA glycosylase activities were again affected differently. After 1 week of dietary ethanol exposure, there was no effect on APNG activity but it was inhibited by 19% at 4 weeks. OXOG glycosylase activity, on the other hand, was increased by 53% after 1 week, but decreased by 40% after 4 weeks. Although some of these changes in DNA repair capacity were relatively small, over time, their potential impact on the repair of endogenous or exogenous alkylation and/or oxidation damage in DNA would be substantial. These studies indicate possible mechanisms for the co-carcinogenic effects of ethanol.
Navasumrit
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P
Cancer Research Campaign Carcinogenesis Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, UK.
Margison
G P
GP
O'Connor
P J
PJ
D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D045647:DNA Glycosylases; D004260:DNA Repair / Q000187:drug effects*; D043382:DNA-Formamidopyrimidine Glycosylase; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000502:physiology; D008297:Male; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002492:Central Nervous System Depressants; D000431:Ethanol; D019853:O(6)-Methylguanine-DNA Methyltransferase; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C076131:DNA-3-methyladenine glycosidase II; D043382:DNA-Formamidopyrimidine Glycosylase