The peroxisome proliferator WY-14,643 promotes hepatocarcinogenesis caused by endogenously generated oxidative DNA base modifications in repair-deficient Csbm/m/Ogg1-/- mice.
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 approximately 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 approximately 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.
Trapp
Christian
C
Institute of Pharmacy, University of Mainz, Mainz, Germany.
Schwarz
Michael
M
Epe
Bernd
B
D000818:Animals; D003043:Cocarcinogenesis; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000172:deficiency / Q000235:genetics; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D000075223:Poly-ADP-Ribose Binding Proteins; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*
C453560:7,8-dihydro-8-oxoguanine; D020025:Peroxisome Proliferators; D000075223:Poly-ADP-Ribose Binding Proteins; D011743:Pyrimidines; D006147:Guanine; C006253:pirinixic acid; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C513075:Ercc6 protein, mouse; D045643:DNA Repair Enzymes