Expression of base excision repair enzymes in rat and mouse liver is induced by peroxisome proliferators and is dependent upon carcinogenic potency

Elevated and sustained cell replication, together with a decrease in apopto sis, is considered to be the main mechanism of hepatic tumor promotion due to peroxisome proliferators, In contrast, the role of oxidative stress and DNA damage in the carcinogenic mechanism is less well understood. In view o f possible induction of DNA damage by peroxisome proliferators, DNA repair mechanisms may be an important factor to consider in the mechanism of actio n of these compounds. Here, the ability of peroxisome proliferators to indu ce expression of base excision repair enzymes was examined. WY-14,643, a po tent carcinogen, increased expression of several base excision DNA repair e nzymes in a dose- and time-dependent manner. Importantly, expression of enz ymes that do not repair oxidative DNA damage was not changed, Moreover, les s potent members of the peroxisome proliferator group had much weaker or no effects on expression of DNA repair enzymes when compared with WY-14,643. Collectively, these data suggest that DNA base excision repair may be an im portant factor in peroxisome proliferator-induced carcinogenesis and that i nduction of DNA repair might provide further evidence supporting a role of oxidative DNA damage by peroxisome proliferators.