Enhanced hepatocarcinogenicity due to agonists of peroxisome proliferator-activated receptors in senescent rats: role of peroxisome proliferation, cell proliferation, and apoptosis.
Enhanced hepatocarcinogenicity due to agonists of peroxisome proliferator-activated receptors in senescent rats: role of peroxisome proliferation, cell proliferation, and apoptosis.
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衰老大鼠中过氧化物酶体增殖物激活受体激动剂增强肝癌性：过氧化物酶体增殖、细胞增殖和凋亡的作用。
DOI：
10.1100/tsw.2002.352
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发表时间：
2002
影响因子：
--
通讯作者：
Badr,Mostafa
中科院分区：
文献类型：
--
作者：
Youssef,Jihan;Badr,Mostafa
暴露于过氧化物酶体增殖物激活受体α(PPARα)激动剂会导致啮齿动物的肝癌，老年动物比年轻动物更容易受到这种影响。与年轻大鼠相比，用这些化学物质治疗老年大鼠产生的肉眼可见的肝脏肿瘤的产量高出五到七倍。老年动物肝脏对PPAR激动剂致癌作用的敏感性增强，不能用幼年动物和老年动物之间过氧化物体和/或细胞增殖水平的差异来解释，因为这些反应都不会随着年龄的增长而夸大。已有研究表明，激活PPARa可抑制肝脏细胞凋亡。这种效应预计会削弱肝脏清除原有肿瘤细胞的能力，使它们能够进展为肿瘤。我们实验室的新发现表明，衰老的肝脏对PPAR激动剂的抗凋亡作用非常敏感。此外，与幼年、成年和中年动物的肝脏相比，老年动物的肝脏显示出显著更高的抗凋亡蛋白Bcl-2水平。有趣的是，PPARa激动剂Wy-14,643显著减少了衰老肝脏中促凋亡机制的元素(如Bax、caspase和fas)，而显著增加了年轻动物中这一机制的元素。综上所述，虽然PPAR的激活似乎抑制了衰老动物肝脏的凋亡，但激活这些受体似乎刺激了年轻动物的凋亡机制。这种矛盾的效应可能是老年肝脏对激活PPAR的致癌作用的夸大敏感的原因。
Exposure to agonists of peroxisome proliferator‐activated receptor alpha (PPARα) causes liver cancer in rodents, with aged animals being more susceptible than their younger counterparts to this effect. Treatment with these chemicals produced a five‐ to sevenfold higher yield of grossly visible hepatic tumors in old rats compared to young animals. The enhanced susceptibility of the aged livers to the carcinogenic effect of PPAR agonists could not be explained by differences in levels of peroxisomal and/or cell proliferation between young and old animals, as neither of these responses was exaggerated with aging. Reported studies have shown that activating PPARa results in the suppression of hepatic apoptosis. This effect is expected to diminish the ability of the liver to purge itself of pre‐existing neoplastic cells, allowing them to progress to tumors. New findings from our laboratories show that the aged liver is exceedingly sensitive to the antiapoptotic effect of PPAR agonists. In addition, aged livers showed remarkably higher levels of the antiapoptotic protein Bcl‐2 than livers of young, adult, and middle‐aged animals. Interestingly, the PPARa agonist Wy‐14,643 significantly diminished elements of the proapoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver, while remarkably increasing elements of this machinery in younger animals. Taken together, while activation of PPARs appears to inhibit apoptosis in livers of senescent animals, activating these receptors seems to stimulate the apoptotic machinery in young animals. This paradoxical effect may be responsible for the exaggerated sensitivity of the aged liver to the carcinogenic effect of agents that activate PPARs.