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A Common Polymorphism in the Bile Acid Receptor Farnesoid X Receptor Is Associated with Decreased Hepatic Target Gene Expression

Marzolini, Catia ; Tirona, Rommel G. ; Gervasini, Guillermo ; [et al.]

The Endocrine Society ; 2007

In: Molecular Endocrinology Vol. 21, No. 8 ( 2007-08-01), p. 1769-1780

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In: Molecular Endocrinology, The Endocrine Society, Vol. 21, No. 8 ( 2007-08-01), p. 1769-1780

Abstract: The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.

Type of Medium: Online Resource

ISSN: 0888-8809 , 1944-9917

URL: Article

DOI: 10.1210/me.2007-0025

Language: English

Publisher: The Endocrine Society

Publication Date: 2007

detail.hit.zdb_id: 1492112-1

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ABCC4 impacts megakaryopoiesis and protects megakaryocytes against 6-mercaptopurine induced cytotoxicity

Ranjit, Sabina ; Wang, Yao ; Zhu, Jingwen ; [et al.]

Elsevier BV ; 2024

In: Drug Resistance Updates Vol. 72 ( 2024-01), p. 101017-

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In: Drug Resistance Updates, Elsevier BV, Vol. 72 ( 2024-01), p. 101017-

Type of Medium: Online Resource

ISSN: 1368-7646

URL: Article

DOI: 10.1016/j.drup.2023.101017

Language: English

Publisher: Elsevier BV

Publication Date: 2024

detail.hit.zdb_id: 2002582-8

SSG: 15,3

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Induction of Cytochrome P4503A by Taxol in Primary Cultures of Human Hepatocytes

Kostrubsky, Vsevolod E. ; Lewis, Lionel D. ; Strom, Stephen C. ; [et al.]

Elsevier BV ; 1998

In: Archives of Biochemistry and Biophysics Vol. 355, No. 2 ( 1998-07), p. 131-136

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In: Archives of Biochemistry and Biophysics, Elsevier BV, Vol. 355, No. 2 ( 1998-07), p. 131-136

Type of Medium: Online Resource

ISSN: 0003-9861

URL: Article

DOI: 10.1006/abbi.1998.0730

RVK:

WA 15000

Language: English

Publisher: Elsevier BV

Publication Date: 1998

detail.hit.zdb_id: 1461378-5

SSG: 12

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Beyond Competitive Inhibition: Regulation of ABC Transporters by Kinases and Protein-Protein Interactions as Potential Mechanisms of Drug-Drug Interactions

Crawford, Rebecca R. ; Potukuchi, Praveen K. ; Schuetz, Erin G. ; [et al.]

American Society for Pharmacology & Experimental Therapeutics (ASPET) ; 2018

In: Drug Metabolism and Disposition Vol. 46, No. 5 ( 2018-05), p. 567-580

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In: Drug Metabolism and Disposition, American Society for Pharmacology & Experimental Therapeutics (ASPET), Vol. 46, No. 5 ( 2018-05), p. 567-580

Type of Medium: Online Resource

ISSN: 0090-9556 , 1521-009X

URL: Article

DOI: 10.1124/dmd.118.080663

Language: English

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Publication Date: 2018

detail.hit.zdb_id: 1500213-5

SSG: 15,3

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Sp1 and Egr-1 Have Opposing Effects on the Regulation of the RatPgp2/mdr1b Gene

Thottassery, Jaideep V. ; Sun, Daxi ; Zambetti, Gerard P. ; [et al.]

Elsevier BV ; 1999

In: Journal of Biological Chemistry Vol. 274, No. 5 ( 1999-01), p. 3199-3206

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In: Journal of Biological Chemistry, Elsevier BV, Vol. 274, No. 5 ( 1999-01), p. 3199-3206

Type of Medium: Online Resource

ISSN: 0021-9258

URL: Article

DOI: 10.1074/jbc.274.5.3199

Language: English

Publisher: Elsevier BV

Publication Date: 1999

detail.hit.zdb_id: 2141744-1

detail.hit.zdb_id: 1474604-9

SSG: 12

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Induction of P-Glycorprotein mRNA by protein synthesis inhibition is not controlled by a transcriptional repressor protein in rat and human liver cells

Schuetz, John D. ; Strom, Stephen C. ; Schuetz, Erin G.

Wiley ; 1995

In: Journal of Cellular Physiology Vol. 165, No. 2 ( 1995-11), p. 261-272

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In: Journal of Cellular Physiology, Wiley, Vol. 165, No. 2 ( 1995-11), p. 261-272

Type of Medium: Online Resource

ISSN: 0021-9541 , 1097-4652

URL: Issue

URL: Journal

URL: Article

DOI: 10.1002/jcp.v165:2

DOI: 10.1002/(ISSN)1097-4652

DOI: 10.1002/jcp.1041650207

Language: English

Publisher: Wiley

Publication Date: 1995

detail.hit.zdb_id: 1478143-8

SSG: 12

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Metabolomic and transcriptomic analysis reveals endogenous substrates and metabolic adaptation in rats lacking Abcg2 and Abcb1a transporters

Ganguly, Samit ; Finkelstein, David ; Shaw, Timothy I. ; [et al.]

Public Library of Science (PLoS) ; 2021

In: PLOS ONE Vol. 16, No. 7 ( 2021-7-13), p. e0253852-

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In: PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 7 ( 2021-7-13), p. e0253852-

Abstract: Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0253852

DOI: 10.1371/journal.pone.0253852.g001

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DOI: 10.1371/journal.pone.0253852.t001

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DOI: 10.1371/journal.pone.0253852.s001

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DOI: 10.1371/journal.pone.0253852.s017

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DOI: 10.1371/journal.pone.0253852.s019

DOI: 10.1371/journal.pone.0253852.s020

DOI: 10.1371/journal.pone.0253852.s021

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2021

detail.hit.zdb_id: 2267670-3

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Isolation of rat pgp3 cDNA: evidence for gender and zonal regulation of expression in the liver

Furuya, Katryn N. ; Gebhardt, Rolf ; Schuetz, Erin G. ; [et al.]

Elsevier BV ; 1994

In: Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression Vol. 1219, No. 3 ( 1994-11), p. 636-644

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In: Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, Elsevier BV, Vol. 1219, No. 3 ( 1994-11), p. 636-644

Type of Medium: Online Resource

ISSN: 0167-4781

URL: Article

DOI: 10.1016/0167-4781(94)90222-4

RVK:

WA 15000

Language: English

Publisher: Elsevier BV

Publication Date: 1994

detail.hit.zdb_id: 2209522-6

SSG: 12

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Divergent effects of cycloheximide on the induction of Class II and Class III cytochrome P450 mRNAs in cultures of adult rat hepatocytes

Burger, Hans-Joerg ; Schuetz, Erin G. ; Schuetz, John D. ; [et al.]

Elsevier BV ; 1990

In: Archives of Biochemistry and Biophysics Vol. 281, No. 2 ( 1990-09), p. 204-211

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In: Archives of Biochemistry and Biophysics, Elsevier BV, Vol. 281, No. 2 ( 1990-09), p. 204-211

Type of Medium: Online Resource

ISSN: 0003-9861

URL: Article

DOI: 10.1016/0003-9861(90)90433-Y

RVK:

WA 15000

Language: English

Publisher: Elsevier BV

Publication Date: 1990

detail.hit.zdb_id: 1461378-5

SSG: 12

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Interactions between Hepatic Mrp4 and Sult2a as Revealed by the Constitutive Androstane Receptor and Mrp4 Knockout Mice

Assem, Mahfoud ; Schuetz, Erin G. ; Leggas, Markos ; [et al.]

Elsevier BV ; 2004

In: Journal of Biological Chemistry Vol. 279, No. 21 ( 2004-05), p. 22250-22257

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In: Journal of Biological Chemistry, Elsevier BV, Vol. 279, No. 21 ( 2004-05), p. 22250-22257

Type of Medium: Online Resource

ISSN: 0021-9258

URL: Article

DOI: 10.1074/jbc.M314111200

Language: English

Publisher: Elsevier BV

Publication Date: 2004

detail.hit.zdb_id: 2141744-1

detail.hit.zdb_id: 1474604-9

SSG: 12

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