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Research ArticleArticle

CYP3A INDUCTION BY LIVER X RECEPTOR LIGANDS IN PRIMARY CULTURED RAT AND MOUSE HEPATOCYTES IS MEDIATED BY THE PREGNANE X RECEPTOR

Sarita D. Shenoy, Thomas A. Spencer, Nancy A. Mercer-Haines, Masumeh Alipour, Mary D. Gargano, Melissa Runge-Morris and Thomas A. Kocarek
Drug Metabolism and Disposition January 2004, 32 (1) 66-71; DOI: https://doi.org/10.1124/dmd.32.1.66
Sarita D. Shenoy
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Thomas A. Spencer
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Nancy A. Mercer-Haines
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Masumeh Alipour
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Mary D. Gargano
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Melissa Runge-Morris
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Thomas A. Kocarek
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Abstract

The effects of oxysterol and drug ligands of the liver X receptor (LXR) on cytochrome P450 expression were evaluated in primary cultured rodent hepatocytes. Treatment of rat hepatocyte cultures with either 25-hydroxycholesterol or 24(S),25-epoxycholesterol (10–5 to 5 × 10–5 M) produced concentration-dependent elevations in CYP3A mRNA and immunoreactive protein levels but did not increase the amounts of CYP1A1, CYP2B, or CYP4A gene products. The effects of 24(S),25-epoxycholesterol on CYP3A content were much greater than were those of 25-hydroxycholesterol, consistent with the relative abilities of these sterols to bind and activate LXR. To understand the mechanistic basis of these observations, experiments were performed using primary cultured hepatocytes prepared from LXRα/β- or pregnane X receptor (PXR)-null mice. CYP3A mRNA levels were increased after treatment with 24(S),25-epoxycholesterol in both wild-type and LXR-null mouse hepatocytes. In contrast, neither 24(S),25-epoxycholesterol nor either of two additional potent LXR ligands, 22(R)-hydroxycholesterol and N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl-]phenyl]-benzenesulfonamide (T0901317), altered CYP3A mRNA levels in hepatocytes prepared from PXR-null mice, although these agents induced CYP3A mRNA content in wild-type cultures. As evidence that the LXR ligands also activated PXR in rat hepatocytes, cotransfection of primary cultures with a dominant negative PXR abolished reporter gene induction after treatment with any of the test agents. These results indicate that selected LXR ligands are capable of activating PXR, probably as a defensive measure to prevent the accumulation of these potentially toxic endogenous molecules.

Footnotes

  • ↵1 Abbreviations used are: LXR, liver X receptor; CAR, constitutive androstane receptor; PXR, pregnane X receptor; P450, cytochrome P450; T0901317, N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide; PCN, pregnenolone 16α-carbonitrile; DMSO, dimethyl sulfoxide; nt, nucleotide; PPARα, peroxisome proliferator-activated receptor α.

  • ↵2 Because the P450 cDNA and antibody probes detect multiple related mRNA or protein species, the specific bands detected on the Northern or Western blot with the CYP2B1, CYP3A1/23, and CYP4A1 probes are referred to as CYP2B, CYP3A, and CYP4A, respectively.

  • This work was supported by National Institutes of Health Sciences grants HL50710 (T.A.K.), HL52069 (T.A.S.), and ES05823 (M.R.-M.) and by services provided by the Cell Culture and Imaging and Cytometry Facility Cores of National Institute of Environmental Health Sciences Center Grant P30 ES06639.

    • Received July 22, 2003.
    • Accepted September 11, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (1)
Drug Metabolism and Disposition
Vol. 32, Issue 1
1 Jan 2004
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Research ArticleArticle

CYP3A INDUCTION BY LIVER X RECEPTOR LIGANDS IN PRIMARY CULTURED RAT AND MOUSE HEPATOCYTES IS MEDIATED BY THE PREGNANE X RECEPTOR

Sarita D. Shenoy, Thomas A. Spencer, Nancy A. Mercer-Haines, Masumeh Alipour, Mary D. Gargano, Melissa Runge-Morris and Thomas A. Kocarek
Drug Metabolism and Disposition January 1, 2004, 32 (1) 66-71; DOI: https://doi.org/10.1124/dmd.32.1.66

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Research ArticleArticle

CYP3A INDUCTION BY LIVER X RECEPTOR LIGANDS IN PRIMARY CULTURED RAT AND MOUSE HEPATOCYTES IS MEDIATED BY THE PREGNANE X RECEPTOR

Sarita D. Shenoy, Thomas A. Spencer, Nancy A. Mercer-Haines, Masumeh Alipour, Mary D. Gargano, Melissa Runge-Morris and Thomas A. Kocarek
Drug Metabolism and Disposition January 1, 2004, 32 (1) 66-71; DOI: https://doi.org/10.1124/dmd.32.1.66
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