氯贝丁酯对猪的治疗：对啮齿动物过氧化物酶体增殖物诱导的肝癌发生相关关键参数的影响。
Clofibrate treatment in pigs: effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents.
作者信息
Luci Sebastian, Giemsa Beatrice, Hause Gerd, Kluge Holger, Eder Klaus
机构信息
Institut für Agrar- und Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany.
出版信息
BMC Pharmacol. 2007 Apr 16;7:6. doi: 10.1186/1471-2210-7-6.
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).
CONCLUSION
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.
背景
在啮齿动物中，用贝特类药物治疗会导致肝癌发生，这可能是氧化应激以及肝脏中细胞凋亡与细胞增殖之间平衡受损的结果。对于贝特类药物是否也能在对过氧化物酶体增殖无反应的物种中诱发肝癌，存在一些争议。在本研究中，研究了氯贝丁酯治疗对猪肝脏中过氧化物酶体增殖、氧化应激产生、促凋亡和抗凋亡基因以及原癌基因的基因表达的影响，猪是一种不过氧化物酶体增殖的物种。
结果
用氯贝丁酯治疗的猪肝脏更重（增加16%），过氧化物酶体数量更多（增加61%），酰基辅酶A氧化酶的mRNA浓度更高（增加66%），过氧化氢酶活性更高（增加41%），但肝脏中过氧化氢浓度更低（降低32%），与对照猪相比差异有统计学意义（P < 0.05）；两组肝脏中脂质过氧化产物（硫代巴比妥酸反应性物质、共轭二烯）以及总谷胱甘肽和还原型谷胱甘肽的浓度无差异。用氯贝丁酯治疗的猪肝脏中bax、原癌基因c-myc和c-jun的mRNA浓度也高于对照猪，而bcl-XL的mRNA浓度低于对照猪（P < 0.05）。
结论
本研究数据表明，氯贝丁酯治疗可诱导猪肝脏中度过氧化物酶体增殖，但不会引起氧化应激。基因表达分析表明，氯贝丁酯治疗并未抑制反而刺激了这些动物肝脏中的细胞凋亡。还表明氯贝丁酯增加了肝脏中原癌基因c-myc和c-jun的表达，这一事件在致癌方面可能至关重要。由于氯贝丁酯引起的过氧化物酶体增殖程度与在人类中观察到的相似，猪可被视为研究过氧化物酶体增殖剂对肝功能和肝癌发生影响的有用模型。
Zotero 插件