Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes

被引:70
作者
Richert, L
Lamboley, C
Viollon-Abadie, C
Grass, P
Hartmann, N
Laurent, S
Heyd, B
Mantion, G
Chibout, SD
Staedtler, F
机构
[1] UFR SMP, Biol Cellulaire Lab, F-25030 Besancon, France
[2] Novartis Pharma AG, Preclin Safety, Pharmacogenom, Basel, Switzerland
[3] Hop Jean Minjoz, Serv Chirurg Digest & Vasc, F-25000 Besancon, France
关键词
rat; mouse; human; primary hepatocyte cultures; clofibric acid; gene expression profiling pharmaco/toxicogenomics;
D O I
10.1016/S0041-008X(03)00231-X
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The mRNA expression profile in control and clofibric acid (CLO)-treated mouse, rat, and human hepatocytes was analyzed using species-specific oligonucleotide DNA microarrays (Affymetrix). A statistical empirical Bayes procedure was applied in order to select the significantly differentially expressed genes. Treatment with the peroxisome proliferator CLO induced up-regulation of genes involved in peroxisome proliferation and in cell proliferation as well as down-regulation of genes involved in apoptosis in hepatocytes of rodent but not of human origin. CLO treatment induced up-regulation of microsomal cytochrome P450 4a genes in rodent hepatocytes and in two of six human hepatocyte cultures. In addition, genes encoding phenobarbital-inducible cytochrome P450s were also up-regulated by CLO in rodent and human hepatocyte cultures. Up-regulation of phenobarbital-inducible UDP-glucuronosyl-transferase genes by CLO was observed in both rat and human but not in mouse hepatocytes. CLO treatment induced up-regulation Of L-fatty acid binding protein (L-FABP) gene in hepatocytes of both rodent and human origin. However, while genes of the cytosolic, microsomal, and mitochondrial pathways involved in fatty acid transport and metabolism were up-regulated by CLO in both rodent and human hepatocyte cultures, genes of the peroxisomal pathway of lipid metabolism were up-regulated in rodents only. An up-regulation of hepatocyte nuclear factor 1alpha (HNF1alpha) by CLO was observed only in human hepatocyte cultures, suggesting that this trans-activating factor may play a key role in the regulation of fatty acid metabolism in human liver as well as in the nonresponsiveness of human liver to CLO-induced regulation of cell proliferation and apoptosis. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:130 / 146
页数:17
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