Formation of 8-oxodeoxyguanosine in liver DNA and hepatic injury by peroxisome proliferator clofibrate and perfluorodecanoic acid in rats.
In this study, we examined whether the production of hydrogen peroxide by peroxisome proliferators causes oxidative DNA damage in the form of 8-oxodeoxyguanosine (8-oxodG) and hepatic injury, and whether it is related to their tumor-promoting or carcinogenic activities in female rats treated with the peroxisome proliferators clofibrate and perfluorodecanoic acid (PFDA). Clofibrate has tumor-promoting and carcinogenic activities, whereas PFDA does not. We also tested whether peroxisome proliferators directly induce mutagenic events in Salmonella typhimurium strains TA 98 and TA 1537. Rats were treated either by 5% clofibrate in diet or by an i.p. injection of corn oil containing 10 mg/kg body weight of PFDA every week for 2 or 8 weeks. 8-OxodG in liver DNA was analyzed by HPLC coupled with an electrochemical detector. Hepatic injury was evidenced by liver enlargement and by levels of serum enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and hepatic gamma-glutamylpeptidase (gamma-GT) activity. Clofibrate and PFDA increased the activity of catalase about or less than 2-fold, whereas FAO activity was increased about 6 to 7-fold by clofibrate and about 3 to 4-fold by PFDA. Neither clofibrate nor PFDA induced mutation at any dose tested. Clofibrate significantly increased the formation of 8-oxodG, but PFDA only slightly increased. Serum AST and ALT levels, and hepatic gamma-GT activity were not significantly changed at both time points, whereas the ratio of liver/body weight was significantly increased by clofibrate and PFDA at 8 weeks. These data imply that the magnitude of the production of hydrogen peroxide-generated FAO is related to the induction of oxidative DNA damage by peroxisome proliferators, and their tumor-promoting or carcinogenic activities. However, the effect of hydrogen peroxide in hepatic injury is not clear.
Kim
S C
SC
College of Pharmacy, Chungbuk National University, Korea.
Hong
J T
JT
Jang
S J
SJ
Kang
W S
WS
Yoo
H S
HS
Yun
Y P
YP
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002273:Carcinogens; D002994:Clofibrate / Q000494:pharmacology*; D004249:DNA Damage / Q000502:physiology*; D003652:Decanoic Acids / Q000494:pharmacology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D005260:Female; D005466:Fluorocarbons / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008830:Microbodies / Q000187:drug effects*; D009152:Mutagenicity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D003652:Decanoic Acids; D005466:Fluorocarbons; C036567:perfluorodecanoic acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine; D002994:Clofibrate