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Evidence against peroxisome proliferation-induced hepatic oxidative damage.

Soliman MS, Cunningham ML, Morrow JD, Roberts LJ, Badr MZ
Biochem Pharmacol. 1997 53 (9): 1369-74

PMID: 9214698 · DOI:10.1016/s0006-2952(97)87956-7

It has been proposed that nongenotoxic peroxisome proliferators may cause hepatocellular cancer by an oxidative damage-mediated mechanism(s). The argument for this hypothesis is based mainly on the noted ability of peroxisome proliferators to induce significantly H2O2-producing peroxisomal beta-oxidation while causing a minimal induction of H2O2-degrading catalase. The recent discovery, accurate determination, and use of isoprostanes as a sensitive indicator of oxidative damage prompted us to investigate whether induction of hepatic peroxisomal beta-oxidation in male B6C3F1 mice is accompanied by elevated levels of isoprostanes in those livers. The data show that while 7 days of feeding mice a diet containing 100 ppm [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643) increased peroxisomal beta-oxidation by 16-fold and catalase activity by only 2-fold, hepatic levels of esterified F2-isoprostanes were not altered. These levels were 2.8 +/- 0.5 ng/g liver in control mice and 2.4 +/- 0.1 ng/g liver in mice fed the experimental diet for 7 days. Consequently, it is concluded that oxidative stress does not appear to occur in response to peroxisome proliferation, as evidenced by the lack of increase in hepatic levels of F2-isoprostanes in livers of mice treated with the potent peroxisome proliferator WY-14,643.

MeSH Terms (12)

Acyl-CoA Dehydrogenase Animals Carcinogens Diet Dinoprost Fatty Acid Desaturases Liver Male Mice Microbodies Oxidative Stress Pyrimidines

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