Passilly P, Jannin B, Hassell S J, Latruffe N
LBMC, University of Burgundy, Dijon, France.
Exp Cell Res. 1996 Mar 15;223(2):436-42. doi: 10.1006/excr.1996.0099.
Peroxisome proliferators, and especially hypolipidemic drugs such as ciprofibrate, are known to be hepatocarcinogens in rodents, but their effect in humans is controversial. In an attempt to investigate the effects of ciprofibrate at a cellular level, the analysis of individual whole cells was performed by flow cytometry on samples from two hepatic-derived cell lines: the rat Fao cell line and the human HepG2 cell line. The increase of light scatter signals in rat Fao cells treated for 3 days with ciprofibrate at 250 microM was related to modifications of intrinsic cellular parameters, such as size and cytoplasmic granularity. Conversely, no variations appeared in human HepG2-treated cells. Moreover, the study of the cell cycle distribution of asynchronously growing cells showed an increase in the percentage of proliferative cells in Fao-treated cells, but not in HepG2-treated cells. In order to give a simultaneous assessment of changes in cellular parameters and cell metabolism, these flow cytometric experiments were completed with the measurements of the palmitoyl-CoA oxidase activity, used as a marker of peroxisome proliferation. The cellular modifications in the rat Fao cell line were accompanied by a great increase in this enzymatic activity, whereas the human HepG2 cell line, which failed to exhibit changes of cytometric data, presented no, or weak, increase in this oxidase activity. The cellular modifications observed in the rat Fao cell line may be related to the well-known hepatocarcinogenicity of ciprofibrate in rodents, whereas the absence of response of HepG2 cells is in favor of the noncarcinogenicity of this drug in humans. This report validates another methodological approach for the investigation of the safety of peroxisome proliferators in humans.
过氧化物酶体增殖剂，尤其是降血脂药物如环丙贝特，在啮齿动物中被认为是肝癌致癌物，但其对人类的影响存在争议。为了在细胞水平上研究环丙贝特的作用，通过流式细胞术对来自两种肝源性细胞系的样本进行了单个全细胞分析：大鼠Fao细胞系和人HepG2细胞系。用250 microM环丙贝特处理3天的大鼠Fao细胞中光散射信号的增加与细胞内在参数的改变有关，如大小和细胞质颗粒度。相反，在人HepG2处理的细胞中未出现变化。此外，对异步生长细胞的细胞周期分布研究表明，Fao处理的细胞中增殖细胞的百分比增加，但HepG2处理的细胞中没有增加。为了同时评估细胞参数和细胞代谢的变化，这些流式细胞术实验通过测量棕榈酰辅酶A氧化酶活性来完成，该活性用作过氧化物酶体增殖的标志物。大鼠Fao细胞系中的细胞改变伴随着该酶活性的大幅增加，而未能表现出细胞计量数据变化的人HepG2细胞系中，该氧化酶活性没有增加或增加微弱。在大鼠Fao细胞系中观察到的细胞改变可能与环丙贝特在啮齿动物中众所周知的肝癌致癌性有关，而HepG2细胞无反应则表明该药物对人类无致癌性。本报告验证了另一种用于研究过氧化物酶体增殖剂对人类安全性的方法学途径。
