Characterization of an Acute Molecular Marker of Nongenotoxic Rodent Hepatocarcinogenesis by Gene Expression Profiling in a Long Term Clofibric Acid Study
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- 作者：Cé ; cile Michel ; Ruth A. Roberts ; Chantal Desdouets ; Kevin R. Isaacs ; and Eric Boitier
- 刊名：Chemical Research in Toxicology
- 出版年：2005
- 出版时间：April 2005
- 年：2005
- 卷：18
- 期：4
- 页码：611 - 618
- 全文大小：228K
- 年卷期：v.18,no.4(April 2005)
- ISSN：1520-5010
文摘
Evaluation of the nongenotoxic potential early during the development of a drug presents a majorchallenge. Recently, two genes were identified as potential molecular markers of rodent hepaticcarcinogenesis: transforming growth factor-
stimulated clone 22 (TSC-22) and NAD(P)H cytochrome P450 oxidoreductase (CYP-R) (1). They were identified after comparing the gene expressionprofiles obtained from the livers of Sprague-Dawley rats treated with different genotoxic andnongenotoxic compounds in a 5 day repeat dose in vivo study. To assess the potential of these twogenes as acute markers of carcinogenesis, we investigated their modulation during a long-termnongenotoxic study in the rat using a classic initiation-promotion regime. Clofibric acid (CLO),which belongs to the broad class of chemicals known as peroxisome proliferators, was used as anongenotoxic hepatocarcinogen. Male F344 rats were given a single nonnecrogenic injection ofdiethylnitrosamine (0 or 30 mg/kg) and fed a diet containing none or 5000 ppm CLO for up to 20months. Necropsies of five rats per groups were performed at 18, 46, 102, 264, 377, 447 (control,DEN, and DEN + CLO rats), 524, and 608 days (for the CLO and control rats). Gross macroscopic andmicroscopic evaluation and gene expression profiling (on Affymetrix microarrays) were performedin peritumoral and tumoral liver tissues. Bioanalysis of the liver gene expression data revealedthat TSC-22 was strongly down-regulated early in the study. Its underexpression was maintainedthroughout the study but disappeared upon CLO withdrawal. These modulations were confirmedby real-time polymerase chain reaction. However, CYP-R gene expression was not significantlyaltered in our study. Taken together, our results showed that TSC-22, but not CYP-R, has thepotential to be an acute early molecular marker for nongenotoxic hepatocarcinogenesis in rodents.
stimulated clone 22 (TSC-22) and NAD(P)H cytochrome P450 oxidoreductase (CYP-R) (1). They were identified after comparing the gene expressionprofiles obtained from the livers of Sprague-Dawley rats treated with different genotoxic andnongenotoxic compounds in a 5 day repeat dose in vivo study. To assess the potential of these twogenes as acute markers of carcinogenesis, we investigated their modulation during a long-termnongenotoxic study in the rat using a classic initiation-promotion regime. Clofibric acid (CLO),which belongs to the broad class of chemicals known as peroxisome proliferators, was used as anongenotoxic hepatocarcinogen. Male F344 rats were given a single nonnecrogenic injection ofdiethylnitrosamine (0 or 30 mg/kg) and fed a diet containing none or 5000 ppm CLO for up to 20months. Necropsies of five rats per groups were performed at 18, 46, 102, 264, 377, 447 (control,DEN, and DEN + CLO rats), 524, and 608 days (for the CLO and control rats). Gross macroscopic andmicroscopic evaluation and gene expression profiling (on Affymetrix microarrays) were performedin peritumoral and tumoral liver tissues. Bioanalysis of the liver gene expression data revealedthat TSC-22 was strongly down-regulated early in the study. Its underexpression was maintainedthroughout the study but disappeared upon CLO withdrawal. These modulations were confirmedby real-time polymerase chain reaction. However, CYP-R gene expression was not significantlyaltered in our study. Taken together, our results showed that TSC-22, but not CYP-R, has thepotential to be an acute early molecular marker for nongenotoxic hepatocarcinogenesis in rodents.