Macdonald N, Chevalier S, Tonge R, Davison M, Rowlinson R, Young J, Rayner S, Roberts R
Syngenta Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Arch Toxicol. 2001 Sep;75(7):415-24. doi: 10.1007/s002040100259.
Peroxisome proliferators (PPs) are a diverse group of chemicals that cause hepatic proliferation, suppression of apoptosis, peroxisome proliferation and liver tumours in rodents. The biochemical response to PPs involves changes in the expression of peroxisomal beta-oxidation enzymes and fatty acid transport proteins such as acyl-CoA oxidase and liver fatty acid binding protein. The response to PPs is mediated by the peroxisome proliferator-activated receptor alpha (PPARalpha) and the livers of PPARalpha-null transgenic mice do not develop tumours in response to PPs. In order to identify the molecular pathways underlying the adverse effects of PPs in rodent liver, we carried out two-dimensional differential gel electrophoresis to provide quantitative proteomic analyses of diethylhexylphthalate (DEHP)-treated wild-type or PPARalpha-null mouse livers. Since tumourigenesis is both PP- and PPARalpha-dependent, analyses were focused on these changes. Fifty-nine proteins were identified where altered expression was both PPARalpha- and PP-dependent. In addition, six proteins regulated by the deletion of PPARalpha were identified, possibly indicating an adaptive change in response to the loss of this receptor. The proteins that we identified as being regulated by PPARalpha are known to be involved in lipid metabolism pathways, but also in amino acid and carbohydrate metabolism, mitochondrial bioenergetics and in stress responses including several genes not previously reported to be regulated by PPARalpha. These data provide novel insights into the pathways utilised by PPs and may assist in the identification of early markers rodent nongenotoxic hepatocarcinogenesis.
过氧化物酶体增殖剂（PPs）是一类多样的化学物质，可导致啮齿动物肝脏增殖、细胞凋亡受抑制、过氧化物酶体增殖及肝肿瘤。对PPs的生化反应涉及过氧化物酶体β-氧化酶和脂肪酸转运蛋白（如酰基辅酶A氧化酶和肝脏脂肪酸结合蛋白）表达的变化。对PPs的反应由过氧化物酶体增殖物激活受体α（PPARα）介导，PPARα基因敲除的转基因小鼠肝脏不会因PPs而发生肿瘤。为了确定PPs对啮齿动物肝脏产生不良影响的分子途径，我们进行了二维差异凝胶电泳，以对邻苯二甲酸二（2-乙基己基）酯（DEHP）处理的野生型或PPARα基因敲除小鼠肝脏进行定量蛋白质组分析。由于肿瘤发生既依赖于PPs也依赖于PPARα，分析集中于这些变化。鉴定出59种蛋白质，其表达改变既依赖于PPARα也依赖于PPs。此外，鉴定出6种受PPARα缺失调控的蛋白质，这可能表明对该受体缺失的适应性变化。我们鉴定出受PPARα调控的蛋白质已知参与脂质代谢途径，也参与氨基酸和碳水化合物代谢、线粒体生物能量学以及应激反应，包括一些以前未报道受PPARα调控的基因。这些数据为PPs所利用的途径提供了新的见解，并可能有助于鉴定啮齿动物非遗传毒性肝癌发生的早期标志物。
