title: Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator.
abstract: The mechanism by which nongenotoxic peroxisome proliferators induce hepatocellular carcinomas in rats and mice remains intriguing. The available experimental evidence suggests that the proliferation of peroxisomes and induction of peroxisome-associated enzymes results in oxidative stress which then leads to tumorigenesis. However, so far no direct evidence for oxidative DNA damage in livers of peroxisome proliferator-treated animals has been established. In the present study we have examined the DNA obtained from the livers of rats treated with ciprofibrate, a potent peroxisome proliferator, for variable periods of time for 8-hydroxydeoxyguanosine (8-OH-dG), an adduct that results from the damage of DNA caused by hydroxyl radical. Administration of ciprofibrate in diet at a concentration of 0.025% for 16, 28, 36, or 40 weeks resulted in progressive increases in the levels of 8-OH-dG. At 16, 28, and 40 weeks of ciprofibrate treatment, the 8-OH-dG in the liver DNA was significantly increased as compared to controls. This increase in 8-OH-dG levels is attributed to persistent peroxisome proliferation resulting from chronic ciprofibrate treatment as no increase in 8-OH-dG was found in liver DNA of rats that received a single large dose of ciprofibrate. The results of this study clearly demonstrate, for the first time, that persistent proliferation of peroxisomes leads to specific oxidative DNA damage.
authors.affiliation: Biology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kasai
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: S
authors.initials: S
authors.lastname: Nishimura
authors.forename: M S
authors.initials: MS
authors.lastname: Rao
authors.forename: J K
authors.initials: JK
authors.lastname: Reddy
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D004247:DNA / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D058607:Fibric Acids; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D058607:Fibric Acids; D002995:Clofibric Acid; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; C019304:ciprofibrate; D003849:Deoxyguanosine; D002994:Clofibrate