Abstract
BackgroundIn 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.ResultsPigs 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).ConclusionThe 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.
Highlights
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
It is shown that clofibrate increases the expression of the proto-oncogenes cmyc 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
Summary
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. Peroxisome proliferators (PPs) comprise a diverse group of chemicals, including pharmaceuticals, industrial chemicals, endogenous fatty acids and eicosanoids. They bind to and activate the peroxisome proliferator-activated receptor (PPAR)-α, a transcription factor belonging to the nuclear hormone receptor superfamily [1]. PPARα-induced hepatocarcinogenesis in rats and mice may be mainly due to an increased oxidative stress caused by peroxisome proliferation and an alteration of the balance between apoptosis and cell proliferation [5,6]. That PPARα is required to mediate hepatocarcinogenesis by PPs has been demonstrated in studies with PPARα-null mice that are refractory to this in response to long term administration of PPs [15,16]
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