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The Peroxisome Proliferator WY-14,643 Promotes Hepatocarcinogenesis Caused by Endogenously Generated Oxidative DNA Base Modifications in Repair-Deficient Csb^m/m/Ogg1^–/– Mice

¹ Institute of Pharmacy, University of Mainz, Mainz, Germany and ² Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tübingen, Tübingen, Germany

Requests for reprints: Bernd Epe, Institute of Pharmacy, University of Mainz, Staudingerweg 5, D-55099 Mainz, Germany. Phone: 49-6131-39-24309; Fax: 49-6131-39-25521; E-mail: epe{at}uni-mainz.de.

Basal levels of endogenously generated oxidative DNA modifications such as 7,8-dihydro-8-oxoguanine (8-oxoG) are present in apparently all mammalian cells, but their relevance for the generation of spontaneous cancers remains to be established. Both the 8-oxoG levels and the resulting spontaneous mutations are increased in the livers of Csb^m/m/Ogg1^–/– mice, which are deficient in the repair of 8-oxoG. In order to determine the consequences of these additional oxidative DNA modifications and mutations and thus assess the tumor initiating potency of this type of endogenous DNA damage, we treated Csb^m/m/Ogg1^–/– mice and repair-proficient controls with the peroxisome proliferator WY-14,643 (0.025% ad libitum), a potent inducer of liver cell proliferation. The treatment did not generate any additional oxidative DNA damage; the elevated levels of 8-oxoG in the Csb^m/m/Ogg1^–/– mice even decreased. Also, the spontaneous mutation frequencies observed in the lacI gene of BigBlue Csb^m/m/Ogg1^–/– mice, which were 3-fold higher than in the repair-proficient mice, declined by 39% under the treatment, whereas the frequencies in the livers of the repair-proficient animals remained unchanged. Preneoplastic lesions (staining positive or negative for glucose-6-phoshatase) developed in the livers of both wild-type and Csb^m/m/Ogg1^–/– mice after 30 weeks. Both the numbers and the total volumes of the lesions were 6-fold higher in the repair-deficient mice than in the wild-type mice. The results indicate that spontaneous mutations generated from endogenous oxidative DNA base damage efficiently translate into increased tumorigenesis when cell proliferation is stimulated. [Cancer Res 2007;67(11):5156–61]

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