Bility Moses T, Thompson Jerry T, McKee Richard H, David Raymond M, Butala John H, Vanden Heuvel John P, Peters Jeffrey M
Department of Veterinary Science and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA.
Toxicol Sci. 2004 Nov;82(1):170-82. doi: 10.1093/toxsci/kfh253. Epub 2004 Aug 13.
Administration of phthalates is known to cause toxicity and liver cancer in rodents through the activation of peroxisome proliferator-activated receptors (PPARs), and the monoesters appear to be the active metabolites that function as ligands of PPARs. There is evidence that PPARs exhibit significant species differences in response to ligand activation. In this study, the activation of mouse and human PPARalpha, PPARbeta, and PPARgamma by a broad class of phthalate monoesters was investigated using a trans-activation assay, functional analysis of PPARalpha target gene expression, and a PPARgamma-mediated differentiation assay. These studies demonstrated a range in the ability of various phthalate monoesters to activate PPARalpha, with the mouse PPARalpha generally being activated at lower concentrations and exhibiting a greater response than human PPARalpha. Similarly, a range in the trans-activation of mouse PPARbeta by phthalate monoesters was also observed, but this effect was not found with human PPARbeta. A number of phthalate monoesters activated both mouse and human PPARgamma, with similar sensitivity being exhibited by both receptors. These studies show that the potency and efficacy of phthalate monoesters for the activation of PPARalpha and PPARgamma increase with increasing side-chain length. These studies also show that mouse PPARalpha and PPARbeta are generally activated at lower concentrations of phthalate monoesters than human PPARalpha and PPARbeta, and that both mouse and human PPARgamma exhibit similar sensitivity to phthalate monoesters. Lastly, there is a good relationship between the relative ability of phthalate monoesters to trans-activate PPARalpha and PPARgamma, and the relative induction of PPARalpha target gene mRNA and PPARgamma-mediated adipocyte differentiation, respectively.
已知邻苯二甲酸酯的给药通过激活过氧化物酶体增殖物激活受体（PPARs）在啮齿动物中引起毒性和肝癌，并且单酯似乎是作为PPARs配体起作用的活性代谢物。有证据表明PPARs在对配体激活的反应中表现出显著的物种差异。在本研究中，使用反式激活测定、PPARα靶基因表达的功能分析和PPARγ介导的分化测定，研究了一大类邻苯二甲酸单酯对小鼠和人PPARα、PPARβ和PPARγ的激活作用。这些研究表明，各种邻苯二甲酸单酯激活PPARα的能力存在差异，小鼠PPARα通常在较低浓度下被激活，并且比人PPARα表现出更大的反应。同样，也观察到邻苯二甲酸单酯对小鼠PPARβ的反式激活存在差异，但人PPARβ未发现这种效应。一些邻苯二甲酸单酯激活了小鼠和人PPARγ，两种受体表现出相似的敏感性。这些研究表明，邻苯二甲酸单酯激活PPARα和PPARγ的效力和功效随着侧链长度的增加而增加。这些研究还表明，与人类PPARα和PPARβ相比，小鼠PPARα和PPARβ通常在较低浓度的邻苯二甲酸单酯下被激活，并且小鼠和人PPARγ对邻苯二甲酸单酯表现出相似的敏感性。最后，邻苯二甲酸单酯反式激活PPARα和PPARγ的相对能力，分别与PPARα靶基因mRNA的相对诱导和PPARγ介导的脂肪细胞分化之间存在良好的关系。
