Phenotypic Anchoring of Global Gene Expression Profiles Induced by N-Hydroxy-4-acetylaminobiphenyl and Benzo[a]pyrene Diol Epoxide Reveals Correlations between Expression Profiles and Mechanism
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- 作者：Wen Luo ; Wenhong Fan ; Hong Xie ; Lichen Jing ; Elaine Ricicki ; Paul Vouros ; Lue Ping Zhao ; and Helmut Zarbl
- 刊名：Chemical Research in Toxicology
- 出版年：2005
- 出版时间：April 2005
- 年：2005
- 卷：18
- 期：4
- 页码：619 - 629
- 全文大小：410K
- 年卷期：v.18,no.4(April 2005)
- ISSN：1520-5010
文摘
The goal of this study was to compare changes in gene expression induced by exposure todifferent carcinogens and to anchor these changes to the induced levels of toxicity andmutagenesis. The human TK6 lymphoblastoid cell line was used as an in vitro model system,and reactive metabolites of two human carcinogens, benzo[a]pyrene and 4-aminobiphenyl, wereused as model compounds. We first determined the toxicity of the model compounds N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and benzo[a]pyrene diol epoxide (BPDE) in TK6 cells.BPDE was about 1000-fold more toxic and mutagenic than N-OH-AABP in TK6 cells on amolar basis. We next treated cells with three doses of each compound that resulted in low,medium, and high toxicities (5, 15, and 40%) and harvested cells at different times afterexposure. Using comparable levels of toxicity as the phenotypic anchor, we compared thepatterns of gene expression induced by each reactive metabolite using printed cDNAmicroarrays comprising ~18 000 human gene/EST sequences. The microarray data from theN-OH-AABP and BPDE treatment groups were compared using self-organizing map clusteringalgorithms, as well as a statistical regression modeling approach. While subsets of genesindicative of a generalized stress response [Hsp 40 homologue (DNAJ), Hsp70, Hsp105, andHsp 125] were detected after exposure to both compounds at all concentrations, there werealso many differentially regulated genes, including phase I xenobiotic metabolism [e.g.,glutathione transferase 
(GSTTLp28) and antioxidant enzymes (Apxl)]. Other differentiallyregulated genes included those encoding proteins involved in all major DNA repair pathways,including excision repair (e.g., ERCC5), mismatch repair (e.g., MLH3), damage specific DNAbinding protein (e.g., DDB2), and cisplatin resistance-associated overexpressed protein (LUC7A,CRA). Differences in the transcriptional response of TK6 cells to N-OH-AABP or BPDE exposuremay explain the dramatic differences in the toxicity and mutagenicity of these humancarcinogens.
(GSTTLp28) and antioxidant enzymes (Apxl)]. Other differentiallyregulated genes included those encoding proteins involved in all major DNA repair pathways,including excision repair (e.g., ERCC5), mismatch repair (e.g., MLH3), damage specific DNAbinding protein (e.g., DDB2), and cisplatin resistance-associated overexpressed protein (LUC7A,CRA). Differences in the transcriptional response of TK6 cells to N-OH-AABP or BPDE exposuremay explain the dramatic differences in the toxicity and mutagenicity of these humancarcinogens.