Hepatocarcinogenesis PPARa activator-induced

Genetically modified mice have been useful to show the relationships between the key events in the PPARa MOA. PPARa-null mice provided critical evidence establishing the rodent MOA for PPARa activator-induced hepatocarcinogenesis. Evidence that a particular compound induces key events in wild-type mice but not in mice lacking PPARa would be considered strong support for a PPARa MOA for that particular compound. To date, three chronic bioassays have been conducted in these mice (Hays et al. 2005 Ito et al. 2007 Peters et al. 1997). A greater body of data exists in which precursor events for cancer have been assessed in wild-type and PPARa-nuU mice after acute or subacute exposures. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

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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