Clofibrate treatment in pigs: effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents.
BACKGROUND
In rodents treatment with fibrates causes hepatocarcinogenesis, probably as a result of oxidative stress and an impaired balance between apoptosis and cell proliferation in the liver. There is some debate whether fibrates could also induce liver cancer in species not responsive to peroxisome proliferation. In this study the effect of clofibrate treatment on peroxisome proliferation, production of oxidative stress, gene expression of pro- and anti-apoptotic genes and proto-oncogenes was investigated in the liver of pigs, a non-proliferating species.


RESULTS
Pigs treated with clofibrate had heavier livers (+16%), higher peroxisome counts (+61%), higher mRNA concentration of acyl-CoA oxidase (+66%), a higher activity of catalase (+41%) but lower concentrations of hydrogen peroxide (-32%) in the liver than control pigs (P < 0.05); concentrations of lipid peroxidation products (thiobarbituric acid-reactive substances, conjugated dienes) and total and reduced glutathione in the liver did not differ between both groups. Clofibrate treated pigs also had higher hepatic mRNA concentrations of bax and the proto-oncogenes c-myc and c-jun and a lower mRNA concentration of bcl-XL than control pigs (P < 0.05).


CONCLUSIONS
The data of this study show that clofibrate treatment induces moderate peroxisome proliferation but does not cause oxidative stress in the liver of pigs. Gene expression analysis indicates that clofibrate treatment did not inhibit but rather stimulated apoptosis in the liver of these animals. It is also shown that clofibrate increases the expression of the proto-oncogenes c-myc and c-jun in the liver, an event which could be critical with respect to carcinogenesis. As the extent of peroxisome proliferation by clofibrate was similar to that observed in humans, the pig can be regarded as a useful model for investigating the effects of peroxisome proliferators on liver function and hepatocarcinogenesis.
Luci
Sebastian
S
Institut für Agrar- und Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany. sebastian.luci@landw.uni-halle.de <sebastian.luci@landw.uni-halle.de>
Giemsa
Beatrice
B
Hause
Gerd
G
Kluge
Holger
H
Eder
Klaus
K
D042962:Acyl-CoA Oxidase / Q000378:metabolism; D000818:Animals; D002994:Clofibrate / Q000009:adverse effects / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D020025:Peroxisome Proliferators / Q000378:metabolism*; D013552:Swine
D000960:Hypolipidemic Agents; D016328:NF-kappa B; D020025:Peroxisome Proliferators; D042962:Acyl-CoA Oxidase; D002994:Clofibrate