Expression in Mice of Human Xenobiotic Drug Metabolizing

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DESCRIPTION (provided by applicant): The premise of the UCSD SBRP states that a toxic episode resulting from exposure to environmental toxicants stems from altered gene control. Activation of the dioxin or AhR plays an important role in the coordination of selective cellular events that lead to bioactivation of toxicants through Phase I cytochrome P450 (CYP)-dependent mechanisms while assuring appropriate cellular protection by induction of Phase II UGT1 glucuronidation pathways. During the past funding period, our laboratory has characterized the full length human CYP1A1 gene as well as the UGT1 locus. To understand the contribution of these genes in defining a toxic event following activation of the AhR, we have developed transgenic mouse lines that carry and express the entire human CYP1A1 gene and the UGT1 locus. With an emphasis in the UCSD SBRP to develop models that can used to identify toxicants, novel mouse strains are being designed that express detectable CYP1A1 or UGT1 luminescent and fluorescent markers that are induced in response to toxicants that activate the AhR. In addition, experiments have been initiated in this application using resources available through the Superfund Core services to .humanize. the CYP1A1 gene and the UGT1 locus in mice with the intention that we will gain valuable insight into the regulatory and humoral responses that link expression of these genes to toxicity. During the course of these studies, it is anticipated that a number of significant biological tools will be developed that can be utilized as biomarkers or resources to examine the contribution of AhR directed toxicants toward gene activation and toxicity. These resources will be exploited by the Research Translation Core and used by this program to determine the feasibility of applying these biological tools as biomarkers for the detection of selective environmental toxicants. The investigators are hopeful that these efforts and future collaborations will further an understanding for the role of the AhR in toxicant induced illnesses.