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.
Division of Toxicology, National Institute of Hygienic Sciences, Tokyo, Japan.
A
A
Takagi
K
K
Sai
T
T
Umemura
R
R
Hasegawa
Y
Y
Kurokawa
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