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Abstract
Characterisation of the pathways by which xenobiotics are metabolised and excreted in both target and non-target organisms is crucial for the rational design of effective and specific novel bioactive molecules. Consequently, we have investigated the induced responses of the model nematode Caenorhabditis elegans to a variety of xenobiotics which represent a range of putative modes of action. The majority of genes that were specifically induced in preliminary microarray analyses encoded enzymes from Phase I and II metabolism, including cytochrome P450s, short chain dehydrogenases, UDP-glucuronosyl transferases and glutathione transferases. Changes in gene expression were confirmed by quantitative PCR and GFP induction in reporter strains driven by promoters for transcription of twelve induced enzymes was investigated. The particular complement of metabolic genes induced was found to be highly contingent on the xenobiotic applied. The known regulators of responses to applied chemicals ahr-1, hif-1, mdt-15 and nhr-8 were not required for any of these inducible responses and skn-1 regulated GFP expression from only two of the promoters. Reporter strains were used in conjunction with systematic RNAi screens to identify transcription factors which drive expression of these genes under xenobiotic exposure. These transcription factors appeared to regulate specific xenobiotic responses and have no reported phenotypes under standard conditions. Focussing on nhr-176 we demonstrate the role of this transcription factor in mediating the resistance to thiabendazole.
Highlights
All organisms regularly encounter exogenous compounds that must be metabolised and excreted
Glutathione transferases (GSTs) and UDP-glucuronosyl transferases (UGTs) catalyse the conjugation reactions which occur in Phase II metabolism
C. elegans were exposed to four xenobiotics and the effects on expression of genes involved in Phase I and Phase II cellular metabolism which had been upregulated $5-fold in preliminary microarray analyses were determined by quantitative real-time PCR (qPCR)
Summary
All organisms regularly encounter exogenous compounds that must be metabolised and excreted. The general molecular mechanism of the metabolic response to such compounds is conserved between species and is divided into three successive phases. In Phase I, functional groups, often hydroxyl groups, are introduced into the xenobiotic compound. These groups are often required for entry into Phase II metabolism, which involves conjugation of these compounds to charged species such as glutathione and sugars for enhanced solubility. The resulting soluble metabolites are excreted by multi-drug efflux pumps, including ATP-binding cassette transporters during Phase III metabolism. Once bound to a xenobiotic, these receptors act as transcription factors and induce the expression of genes that encode metabolic enzymes and components of multi-drug efflux pumps (reviewed in [1])
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