Novel role of oxidants in the molecular mechanism of action of peroxisome proliferators.
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Peroxisome proliferators are nongenotoxic rodent carcinogens that act as tumor promoters by increasing cell proliferation; however, their precise mechanism of action is not well understood. Oxidative DNA damage caused by leakage of hydrogen peroxide (H2O2) from peroxisomes was hypothesized initially as the mechanism by which these compounds cause liver tumors. It seems unlikely that oxidants of peroxisomal origin explain the mechanism of action of peroxisome proliferators because treatment with these compounds in vivo does not lead to increased H2O2 production. On the other hand, Kupffer cell-derived oxidants, such as superoxide, may play a role in initiating tumor nerosis factor-alpha (TNF-alpha) production that leads to hepatocyte proliferation. Peroxisome proliferators have been shown to activate Kupffer cells both in vitro and in vivo, and the use of Kupffer cell inhibitors such as methyl palmitate and dietary glycine have demonstrated that Kupffer cells are responsible for hepatocyte proliferation by mechanisms involve TNF-alpha. Moreover, peroxisome proliferators activate the transcription factor NF-kappaB, one of the major regulators of TNF-alpha expression, in Kupffer cells. Importantly, activation of NF-kappaB by peroxisome proliferators was shown to be oxidant-dependent, leading to the hypothesis that oxidants of Kupffer cell origin are involved in the mechanism of action. Many of the effects of peroxisome proliferators, including peroxisome induction and hepatomegaly, involve the peroxisome proliferator-activated receptor-alpha (PPARalpha). Recently, it was shown that peroxisome proliferator-induced cell proliferation and tumors require the PPARalpha. However, PPARalpha is not involved in TNF-alpha production by Kupffer cells because it is not expressed in this cell type. How it is involved in liver tumor remains unclear and one possible explanation is that both Kupffer cell TNF-alpha and parenchymal cell PPARalpha are required. Collectively, recent data are consistent with the hypothesis that oxidants play a role in signaling hepatocellular proliferation due to peroxisome proliferators via activation of NF-kappaB and incrase in mitogenic cytokines such as TNF-alpha.