Exposure studies PPARa activator

Overall, PPARa activators increase the level of oxidative stress through multiple mechanisms. There is httle direct evidence that increases in oxidative stress generated after PPARa activator exposure leads to direct or indirect DNA damage. The Oggl-null mouse studies indicate that PPARa activators promote hepatocytes that have been spontaneously initiated. The WOE snggests that direct or oxidatively induced DNA damage is not part of the MO A. 

A chronic (38-week) exposure study provides direct evidence that NF-kB activation is necessary for hepatocarcinogenesis induced by a PPARa activator (Glauert et al. 2006). Wild-type mice receiving only DEN developed a low incidence of tumors (25%). The majority of wild-type mice receiving both DEN -i- WY-14,643 developed tumors (63%). However, no tumors were seen in the DEN or DEN -i- WY-14,643-treated p50-null mice, demonstrating that the p50 subunit of NF-kB was required for the promotion of hepatic tumors by WY-14,643. Treatment with DEN -I- WY-14,643 increased both cell proliferation and apoptosis in wild-type and p50-null mice. Consistent with the tumor levels, cell proliferation and apoptosis were lower in the p50-nuU mice than in wild-type mice (Glauert et al. 2006). This study shows direct dependence on the p50 subunit of NF-kB for liver tumor induction by a PPARa activator. 

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