cDNA microarray gene expression profiling of hydroxyurea, paclitaxel, and p-anisidine, genotoxic compounds with differing tumorigenicity results.
The potential application of toxicogenomics to predictive toxicology has been discussed widely, but the utility of the approach remains largely unproven. Using cDNA microarrays, we compared the gene expression profiles produced in mouse lymphoma cells by three genotoxic compounds, hydroxyurea (a carcinogen), p-anisidine (a noncarcinogen), and paclitaxel (carcinogenicity unknown). To minimize the effect of biological variability and technological limitations, quadruplicate observations were made for each compound and a subset of genes yielding reproducible induction/repression was selected for comparison. A method was applied to attach normalized expression data to genes with a low false-discovery rate (<0.1) to yield more confidence regarding differential expression. This analysis identified genotoxicity-specific gene expression. Seven genes were consistently upregulated and 12 downregulated more than 2-fold by the three genotoxic compounds. Using additional genes, the expression pattern induced by the genotoxic noncarcinogen, p-anisidine, was readily distinguished from that associated with the genotoxic carcinogen, hydroxyurea. Comparison of paclitaxel-induced expression data to data for p-anisidine and hydroxyurea suggested that paclitaxel's profile is more similar to the genotoxic noncarcinogen. With further supporting evidence it may be possible to perform large-scale monitoring of gene expression during drug and chemical development that can provide an early warning of potential toxicological responses.
Lee
Michael
M
Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yusong, Daejeon, Republic of Korea. mikelee@kitox.re.kr
Kwon
Jung
J
Kim
Se Nyun
SN
Kim
Ja Eun
JE
Koh
Woo Suk
WS
Kim
Eun-Joo
EJ
Chung
Moon-Koo
MK
Han
Sang-Seop
SS
Song
Chang Woo
CW
D000814:Aniline Compounds / Q000633:toxicity*; D000818:Animals; D004249:DNA Damage; D020869:Gene Expression Profiling / Q000379:methods*; D006918:Hydroxyurea / Q000633:toxicity*; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D000814:Aniline Compounds; C013813:4-anisidine; D017239:Paclitaxel; D006918:Hydroxyurea