NUCLEAR RECEPTOR REGULATION OF THE C ELEGANS DETOXIFICATION NETWORK

Univ Of Arkansas For Med Scis, Little Rock AR

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long term goal of this research is to understand how environmental chemical signals impact the expression of drug metabolism enzymes (DMEs). Although it is recognized that DME gene expression is upregulated in the presence of their substrates, insights into the mechanisms of this induction have only recently been obtained. The nuclear receptor (NR) PXR has been implicated as a key mediator of xenobiotic induction of DME expression in several vertebrate species. This discovery broadened the known biology attributed to the NR superfamily;namely, that NRs not only regulate transcription in response to endogenous signals but also in response to the presence of chemical signals from the environment. To date, searches for transcriptional targets for PXR and other "xenobiotic sensing" NRs have generally revealed members of DME gene families. Thus, discovery of the entire suite of genes regulated by these NRs will illuminate the various metabolic pathways elicited by xenobiotics. This knowledge, in turn, will provide the requisite information needed for the prediction of drug-drug and drug-environment interactions that often result in dramatically modified efficacy of prescription drugs. The discovery of NR regulated DME expression, coupled with the advent of genome sequencing projects and modern genomics tools, makes the use of a toxicogenomics approach to reveal the complete description of loci upregulated via NRs in response to compounds in our drugs, diet, and environment an appealing possibility. Within the C. elegans genome are more than 260 NRs including several that are closely related to PXR. Among these PXR-related NRs is NHR-8, which C. elegans requires for wild type resistance to xenobiotics. The role of NHR-8 in xenobiotic resistance suggests that like its vertebrate homolog, NHR-8 responds to the presence of xenobiotic toxic compounds by upregulating the expression of a detoxification network to remove the offending compounds.