Mutagen structure and transcriptional response: induction of distinct transcriptional profiles in Salmonella TA100 by the drinking-water mutagen MX and its homologues.
The relationship between chemical structure and biological activity has been examined for various compounds and endpoints for decades. To explore this question relative to global gene expression, we performed microarray analysis of Salmonella TA100 after treatment under conditions of mutagenesis by the drinking-water mutagen MX and two of its structural homologues, BA-1, and BA-4. Approximately 50% of the genes expressed differentially following MX treatment were unique to MX; the corresponding percentages for BA-1 and BA-4 were 91 and 80, respectively. Among these mutagens, there was no overlap of altered Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or RegulonDB regulons. Among the 25 Comprehensive Microbial Resource functions altered by these mutagens, only four were altered by more than one mutagen. Thus, the three structural homologues produced distinctly different transcriptional profiles, with none having a single altered KEGG pathway in common. We tested whether structural similarity between a xenobiotic and endogenous metabolites could explain transcriptional changes. For the 830 intracellular metabolites in Salmonella that we examined, BA-1 had a high degree of structural similarity to 2-isopropylmaleate, which is the substrate for isopropylmalate isomerase. The transcription of the gene for this enzyme was suppressed twofold in BA-1-treated cells. Finally, the distinct transcriptional responses of the three structural homologues were not predicted by a set of phenotypic anchors, including mutagenic potency, cytotoxicity, mutation spectra, and physicochemical properties. Ultimately, explanations for varying transcriptional responses induced by compounds with similar structures await an improved understanding of the interactions between small molecules and the cellular machinery.
Ward
William O
WO
Integrated Systems Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Swartz
Carol D
CD
Hanley
Nancy M
NM
Whitaker
John W
JW
Franzén
Robert
R
DeMarini
David M
DM
D005663:Furans / Q000737:chemistry / Q000633:toxicity*; D046228:Microarray Analysis; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D012475:Salmonella / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D014867:Water / Q000737:chemistry; D014881:Water Supply
D005663:Furans; D009153:Mutagens; D014157:Transcription Factors; D014867:Water; C006646:N-(2-cyanoethylene)urea; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; D014508:Urea