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. Drug-induced hepatotoxicity is generally presented as cholestasis, hepatitis, or both. Cholestasis is caused by impaired bile flow and exhibits a series of bile-stagnated symptoms. Many drugs have been found to induce cholestasis. Although many factors likely contribute to cholestasis, disrupted canalicular secretion is recently recognized as a major determinant factor. Genetic and biochemical studies have established that the bile salt export pump (BSEP) is responsible for the secretion of bile acids. Decreased or defective BSEP function is linked directly to hereditary and acquired cholestasis. The long-term goal of the proposed project is to test the hypothesis that the regulated expression of the BSEP by xenobiotics is achieved by transcription regulation through distinct but functionally related nuclear receptor pathways.
The specific aims of this pilot project include: (1) to determine the regulatory modes of BSEP expression by xenobiotics; and (2) to locate cis-acting elements in the BSEP promoter responsible for the regulated expression of BSEP by those chemicals. The first specific aim is designed to test the hypothesis that the regulated expression of BSEP by these chemicals is achieved by either altering transcription rate or mRNA stability. Two experimental approaches are proposed to test this hypothesis: (a) dose-response and time course studies will be conducted with these chemicals; (b) and cells will be co-treated with xenobiotics and transcription inhibitors, and the level of BSEP mRNA will be monitored. The second specific aim is designed to test the hypothesis that transcription regulation of BSEP by these chemicals is sequence-specific. Two experimental approaches are designed to test the hypothesis: (a) A BSEP promoter containing potential xenobiotic-response elements will be prepared and tested for the responsiveness to these chemicals; and (b) deletion mutants of the BSEP promoter will be made to locate functionally important sequences for the regulated expression.
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