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Novel Role of Oxidants in the Molecular Mechanism of Action of Peroxisome Proliferators



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ANTIOXIDANTS REDOX SIGNALING Volume 2 Number 3 2000 Mary Ann Liebert Inc Review Article Novel Role of Oxidants in the Molecular Mechanism of Action of Peroxisome Proliferators IVAN RUSYN MICHELLE L ROSE HEIDI K BOJES and RONALD G THURMAN ABSTRACT 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 H2O 2 production On the other hand Kupffer cell derived oxidants such as superoxide may play a role in initiating tumor nerosis factor a TNF a 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 a Moreover peroxisome proliferators activate the transcription factor NFkB one of the major regulators of TNF a expression in Kupffer cells Importantly activation of NF kB 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 a PPARa Recently it was shown that peroxisome proliferator induced cell proliferation and tumors require the PPARa However PPARa is not involved in TNF a production by Kupffer cells because it is not expressed in this cell type How it is



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