Altered expression of small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 induction during Pregnancy in CYP2D6-humanized mice

Kwi Hye Koh, Xian Pan, Hong Wu Shen, Samuel L M Arnold, Aiming Yu, Frank J. Gonzalez, Nina Isoherranen, Hyunyoung Jeong

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women. Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg- CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4δ (HNF4δ), did not change during pregnancy. However, HNF4δ recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4δ transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.

Original languageEnglish (US)
Pages (from-to)3105-3113
Number of pages9
JournalJournal of Biological Chemistry
Volume289
Issue number6
DOIs
StatePublished - Feb 7 2014

Fingerprint

Cytochrome P-450 CYP2D6
Pregnancy
Hepatocyte Nuclear Factor 4
Transgenic Mice
Liver
Tretinoin
Metabolism
Pregnant Women
Pharmaceutical Preparations
Drug therapy

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Altered expression of small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 induction during Pregnancy in CYP2D6-humanized mice. / Koh, Kwi Hye; Pan, Xian; Shen, Hong Wu; Arnold, Samuel L M; Yu, Aiming; Gonzalez, Frank J.; Isoherranen, Nina; Jeong, Hyunyoung.

In: Journal of Biological Chemistry, Vol. 289, No. 6, 07.02.2014, p. 3105-3113.

Research output: Contribution to journalArticle

Koh, Kwi Hye ; Pan, Xian ; Shen, Hong Wu ; Arnold, Samuel L M ; Yu, Aiming ; Gonzalez, Frank J. ; Isoherranen, Nina ; Jeong, Hyunyoung. / Altered expression of small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 induction during Pregnancy in CYP2D6-humanized mice. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 6. pp. 3105-3113.
@article{66ccf9e985234dc19577cb712ffd81ce,
title = "Altered expression of small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 induction during Pregnancy in CYP2D6-humanized mice",
abstract = "Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women. Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg- CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4δ (HNF4δ), did not change during pregnancy. However, HNF4δ recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4δ transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.",
author = "Koh, {Kwi Hye} and Xian Pan and Shen, {Hong Wu} and Arnold, {Samuel L M} and Aiming Yu and Gonzalez, {Frank J.} and Nina Isoherranen and Hyunyoung Jeong",
year = "2014",
month = "2",
day = "7",
doi = "10.1074/jbc.M113.526798",
language = "English (US)",
volume = "289",
pages = "3105--3113",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - Altered expression of small Heterodimer Partner Governs Cytochrome P450 (CYP) 2D6 induction during Pregnancy in CYP2D6-humanized mice

AU - Koh, Kwi Hye

AU - Pan, Xian

AU - Shen, Hong Wu

AU - Arnold, Samuel L M

AU - Yu, Aiming

AU - Gonzalez, Frank J.

AU - Isoherranen, Nina

AU - Jeong, Hyunyoung

PY - 2014/2/7

Y1 - 2014/2/7

N2 - Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women. Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg- CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4δ (HNF4δ), did not change during pregnancy. However, HNF4δ recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4δ transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.

AB - Background: CYP2D6-mediated drug metabolism is enhanced during pregnancy, but the underlying mechanisms remain unknown. Results: In CYP2D6-humanized mice, CYP2D6 induction during pregnancy was linked to decreased expression of SHP, a repressor of CYP2D6 expression. Conclusion: Decreased SHP expression may account for CYP2D6 induction during pregnancy. Significance: This may provide a mechanistic basis in designing optimal dosage regimens in pregnant women. Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg- CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4δ (HNF4δ), did not change during pregnancy. However, HNF4δ recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4δ transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.

UR - http://www.scopus.com/inward/record.url?scp=84893704468&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893704468&partnerID=8YFLogxK

U2 - 10.1074/jbc.M113.526798

DO - 10.1074/jbc.M113.526798

M3 - Article

C2 - 24318876

AN - SCOPUS:84893704468

VL - 289

SP - 3105

EP - 3113

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -