Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells.
Large doses of acetaminophen (APAP) could cause oxidative stress and tissue damage through production of reactive oxygen/nitrogen (ROS/RNS) species and quinone metabolites of APAP. Although ROS/RNS are known to modify DNA, the effect of APAP on DNA modifications has not been studied systematically. In this study, we investigate whether large doses of APAP can modify the nuclear DNA in C6 glioma cells used as a model system, because these cells contain cytochrome p450-related enzymes responsible for APAP metabolism and subsequent toxicity (Geng and Strobel, 1995). Our results revealed that APAP produced ROS and significantly elevated the 8-oxo- deoxyguanosine (8-oxodG) levels in the nucleus of C6 glioma cells in a time and concentration dependent manner. APAP significantly reduced the 8- oxodG incision activity in the nucleus by decreasing the activity and content of a DNA repair enzyme, Ogg1. These results indicate that APAP in large doses can increase the 8-oxodG level partly through significant reduction of Ogg1 DNA repair enzyme.
Wan
Jie
J
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism NIH, 12420 Parklawn Drive, Rockville, MD 20852, USA.
Bae
Myung-Ae
MA
Song
Byoung-Joon
BJ
D000082:Acetaminophen / Q000378:metabolism*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D003849:Deoxyguanosine / Q000737:chemistry / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D004247:DNA; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D003849:Deoxyguanosine; D005978:Glutathione