Evidence map›Paper›PMID 34011532›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2021

Negative Regulation of Human Hepatic Constitutive Androstane Receptor by Cholesterol Synthesis Inhibition: Role of Sterol Regulatory Element Binding Proteins.

Liberta Cuko, Zofia Duniec-Dmuchowski, Elizabeth A Rondini, Asmita Pant, John K Fallon, Elizabeth M Wilson, Nicholas J Peraino, Judy A Westrick, Philip C Smith, Thomas A Kocarek

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.2field-weighted citation impact, top 50% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 2 citations in OpenAlex.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 1 country.

Liberta CukoInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Zofia Duniec-DmuchowskiInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Elizabeth A RondiniInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Asmita PantInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
John K FallonInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Elizabeth M WilsonInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Nicholas J PerainoInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Judy A WestrickInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Philip C SmithInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.).
Thomas A KocarekInstitute of Environmental Health Sciences (L.C., Z.D.-D., E.A.R., A.P., T.A.K.) and Department of Chemistry (N.J.P., J.A.W.), Wayne State University, Detroit, Michigan; Division of Pharmacoengineering and Molecular Pharmaceutics, University of North Carolina, Chapel Hill, North Carolina (J.K.F., P.C.S.); and Yecuris Corporation, Tualatin, Oregon (E.M.W.) t.kocarek@wayne.edu.
University of North Carolina at Chapel Hill · USWayne State University · USYecuris (United States) · US

Funding

Pilot Project ProgramP30ES020957 · NIEHS · WAYNE STATE UNIVERSITY · PI RUDEN, DOUGLAS M · 2014 to 2021
$10.1M
REGULATION OF HEPATIC P450S BY ANTICHOLESTEROL DRUGSR01HL050710 · NHLBI · WAYNE STATE UNIVERSITY · PI KOCAREK, THOMAS A · 1999 to 2020
$5.3M
Shared UPLC-MS/MS for Absolute Quantitative ProteomicsS10RR024595 · NCRR · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SMITH, PHILIP C · 2008 to 2008
$381k
NCRR NIH HHS S10 RR024595NHLBI NIH HHS R01 HL050710NIDDK NIH HHS HHSN267200700004CNIEHS NIH HHS P30 ES020957NLM NIH HHS HHSN267200700004G
6 · The paper itself

Abstract

The squalene synthase inhibitor squalestatin 1 (Squal1) is a potent and efficacious inducer of CYP2B expression in primary cultured rat hepatocytes and rat liver. To determine whether Squal1 is also an inducer of human CYP2B, the effects of Squal1 treatment were evaluated in primary cultured human hepatocytes, differentiated HepaRG cells, and humanized mouse livers. Squal1 treatment did not increase CYP2B6 mRNA levels in human hepatocytes or HepaRG cells and only slightly and inconsistently increased CYP2B6 mRNA content in humanized mouse liver. However, treatment with farnesol, which mediates Squal1's effect on rat CYP2B expression, increased CYP2B6 mRNA levels in HepaRG cells expressing the constitutive androstane receptor (CAR), but not in cells with knocked-down CAR. To determine the impact of cholesterol biosynthesis inhibition on CAR activation, the effects of pravastatin (Prava) were determined on CITCO-mediated gene expression in primary cultured human hepatocytes. Prava treatment abolished CITCO-inducible CYP2B6 expression, but had less effect on rifampicin-mediated CYP3A4 induction, and CITCO treatment did not affect Prava-inducible HMG-CoA reductase (HMGCR) expression. Treatment with inhibitors of different steps of cholesterol biosynthesis attenuated CITCO-mediated CYP2B6 induction in HepaRG cells, and Prava treatment increased HMGCR expression and inhibited CYP2B6 induction with comparable potency. Transfection of HepG2 cells with transcriptionally active sterol regulatory element binding proteins (SREBPs) reduced CAR-mediated transactivation, and inducible expression of transcriptionally active SREBP2 attenuated CITCO-inducible CYP2B6 expression in HepaRG cells. These findings suggest that Squal1 does not induce CYP2B6 in human hepatocytes because Squal1's inhibitory effect on cholesterol biosynthesis interferes with CAR activation. SIGNIFICANCE STATEMENT: The cholesterol biosynthesis inhibitor squalestatin 1 induces rat hepatic CYP2B expression indirectly by causing accumulation of an endogenous isoprenoid that activates the constitutive androstane receptor (CAR). This study demonstrates that squalestatin 1 does not similarly induce CYP2B6 expression in human hepatocytes. Rather, inhibition of cholesterol biosynthesis interferes with CAR activity, likely by activating sterol regulatory element binding proteins. These findings increase our understanding of the endogenous processes that modulate human drug-metabolizing gene expression.

Indexed as

AnimalsAnticholesteremic AgentsBridged Bicyclo Compounds, HeterocyclicCell LineCholesterolConstitutive Androstane ReceptorCytochrome P-450 CYP2B6Cytochrome P-450 CYP2D6FarnesolGene Expression Regulation, EnzymologicGene Knockdown TechniquesHepatocytesHumansLiverMicePravastatinAnticholesteremic AgentsBridged Bicyclo Compounds, HeterocyclicCholesterolConstitutive Androstane ReceptorCytochrome P-450 CYP2B6Cytochrome P-450 CYP2D6FarnesolPravastatinsqualestatin 1Sterol Regulatory Element Binding ProteinsTricarboxylic Acids

Identifiers

PMID34011532
PMCPMC11025015
OpenAlexW3160427539

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.