Relationship between hepatic peroxisome proliferation and 8-hydroxydeoxyguanosine formation in liver DNA of rats following long-term exposure to three peroxisome proliferators; di(2-ethylhexyl) phthalate, aluminium clofibrate and simfibrate.
To elucidate the relationship between hepatic peroxisome proliferation and oxidative DNA damage induced by hepatocarcinogenic peroxisome proliferators, 3 agents, namely, di(2-ethylhexyl) phthalate (DEHP, aluminium clofibrate and simfibrate were fed at doses of 1.2%, aluminium clofibrate 0.5% and 0.5% in the diet, respectively, to male F-344 rats for up to 1 year. Evidence of hepatic peroxisome proliferation and 8-hydroxydeoxyguanosine (8-OH-dG) formation in liver and kidney DNA were assessed at 1, 2, 3, 6, 9 and 12 months. Peroxisomal beta-oxidation enzyme activities were increased 3- to 8-fold and catalase was elevated to 1.4- to 2.2-fold the control level by DEHP, aluminium clofibrate and simfibrate from months 1 to 12 of the treatment. 8-OH-dG levels in liver DNA of DEHP-, aluminium clofibrate- and simfibrate-fed rats were increased approximately 2-fold after 1 month, the tendency for elevation also being observed in the liver DNA at 2, 3, 9 and 12 months. The results thus clearly demonstrate that persistent peroxisome proliferation in the liver leads to continued specific oxidative DNA damage.
Takagi
A
A
Division of Toxicology, National Institute of Hygienic Sciences, Tokyo, Japan.
Sai
K
K
Umemura
T
T
Hasegawa
R
R
Kurokawa
Y
Y
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000535:Aluminum / Q000633:toxicity; D000818:Animals; D002374:Catalase / Q000378:metabolism; D002994:Clofibrate / Q000031:analogs & derivatives* / Q000633:toxicity*; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D003643:Death; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D000960:Hypolipidemic Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008830:Microbodies / Q000378:metabolism / Q000502:physiology*; D010084:Oxidation-Reduction; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D013997:Time Factors
D000960:Hypolipidemic Agents; D010795:Phthalic Acids; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D004051:Diethylhexyl Phthalate; D000535:Aluminum; D002374:Catalase; D003849:Deoxyguanosine; D002994:Clofibrate; C003278:simfibrate