Evidence against peroxisome proliferation-induced hepatic oxidative damage.
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.
Soliman
M S
MS
Division of Pharmacology, University of Missouri-Kansas City, 64108, U.S.A.
Cunningham
M L
ML
Morrow
J D
JD
Roberts
L J
LJ
Badr
M Z
MZ
D042964:Acyl-CoA Dehydrogenase; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D004032:Diet; D015237:Dinoprost / Q000031:analogs & derivatives / Q000378:metabolism; D044943:Fatty Acid Desaturases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008830:Microbodies / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*
D002273:Carcinogens; D011743:Pyrimidines; C006253:pirinixic acid; D015237:Dinoprost; D044943:Fatty Acid Desaturases; D042964:Acyl-CoA Dehydrogenase