TAILIEUCHUNG - Báo cáo Y học: Functional analysis of the rat bile salt export pump gene promoter Regulation by bile acids, drugs and endogenous compounds

The 5¢ flanking region of the bile salt export pump (Bsep) gene was systematically analysed to provide the basis for understanding the mechanisms which regulate Bsep transcription. In addition substrates and drugs were investigated for their ability to alter Bsep promoter activity. Bsep promoter function was restricted to hepatocyte derived HepG2 cells. The 5¢ deletional analysis revealed a biphasic shape of reporter gene activities, indicating a suppressive element between nucleotides )800 and )512. . | Eur. J. Biochem. 269 3495-3503 2002 FEBS 2002 doi Functional analysis of the rat bile salt export pump gene promoter Regulation by bile acids drugs and endogenous compounds Thomas Gerloff1 Andreas Geier2 Ivar Roots1 Peter J. Meier3 and Carsten Gartuna2 . Institute of Clinical Pharmacology Charite University Medical Center Humboldt University Berlin Germany department of Internal Medicine Aachen University of Technology Aachen Germany 3Division of Clinical Pharmacology and Toxicology Department of Medicine University Hospital Zurich Switzerland The 5 flanking region of the bile salt export pump Bsep gene was systematically analysed to provide the basis for understanding the mechanisms which regulate Bsep transcription. In addition substrates and drugs were investigated for their ability to alter Bsep promoter activity. Bsep promoter function was restricted to hepatocyte derived HepG2 cells. The 5 deletional analysis revealed a biphasic shape of reporter gene activities indicating a suppressive element between nucleotides -800 and -512. Two consensus sites for the farnesoid X receptor FXR were located at nucleotides -473 and -64. The latter was characterized as functionally active in bile acid-mediated feed-back regulation of Bsep transcription. Bsep promoter activity was reduced by rifampin and b-estradiol. The anti-estrogen tamoxifen stimulated promoter activity. Dexamethasone hydrocortisone and phenobarbital had no effect on Bsep promoter activity. In conclusion the data suggest that transcriptional regulation of the Bsep gene can be modulated by a number of endogenous compounds and xenobiotics. FXR was a major regulatory factor mediating bile acid feed-back stimulation of Bsep transcription. Keywords bile flow drug-induced cholestasis transcriptional regulation. Bile secretion by vertebrate liver is caused by the continuous vectorial excretion of bile acids and other osmotically active substrates across the canalicular pole of .

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