Regulation of CYP2C19 Expression by Estrogen Receptor α: Implications for Estrogen-Dependent Inhibition of Drug Metabolism

Mwinyi, Jessica; Cavaco, Isabel; Pedersen, Robert Smith; Persson, Anna; Burkhardt, Sabrina; Mkrtchian, Souren; Ingelman‐Sundberg, Magnus

doi:10.1124/mol.110.065540

Cited by 52 publications

(48 citation statements)

References 35 publications

(42 reference statements)

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“…It seems that ER␣-dependent transcriptional regulation is rather well conserved in the CYP2C subfamily because we were able to report a similar regulatory mechanism for CYP2C19 (Mwinyi et al, 2010a). The functionally relevant ERE half-site detected in the CYP2C19 promoter is apparently the conserved analog of the ERE half-site described here, as confirmed by the alignment of corresponding fragments (not shown).…”

Section: Discussionsupporting

confidence: 78%

The Ligands of Estrogen Receptor α Regulate Cytochrome P4502C9 (CYP2C9) Expression

Mwinyi¹,

Cavaco²,

Yurdakok³

et al. 2011

J Pharmacol Exp Ther

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Cytochrome P4502C9 (CYP2C9) is an important drug-metabolizing enzyme responsible for the metabolism of approximately 16% of all clinically relevant drugs. It was shown previously that the activity of CYP2C9 in vivo is inhibited by oral contraceptives. The mechanisms of this effect have not been elucidated. We hypothesize that this may occur because of the sex steroid-dependent activation of estrogen receptor ␣ (ER␣) with further transactivation of the CYP2C9 gene. Here, we show that the CYP2C9 promoter indeed contains a functionally relevant estrogen responsive element (ERE) half-site at position Ϫ149/Ϫ145. Its ER␣ binding activity was tested by the luciferase gene reporter assay. Promoter constructs bearing this site were cotransfected with ER␣ into Huh7 hepatoma cells and treated with various ER␣ ligands including 4-hydroxytamoxifen (4-OHT), raloxifene (R), 17␤-estradiol (EE), and 17␣-ethinylestradiol (ETE). The luciferase activity driven by the wild-type CYP2C9 promoter construct was up-regulated by 4-OHT and R and significantly or marginally suppressed by ETE and EE, respectively. An identical effect was observed in primary hepatocytes treated with these compounds. Mutations introduced into the ERE half-site abolished the observed effects in the Huh7 cells. Electrophoretic mobility-shift assay revealed sequencespecific binding of a nuclear protein to the oligonucleotide containing the ERE half-site, which was identified as ER␣ by antibody supershift analysis. In addition, the association of ER␣ with CYP2C9 promoter was strongly supported by chromatin immunoprecipitation data. Taken together, these results indicate that ER␣ and its ligands play an important role in the regulation of CYP2C9 expression.

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Section: Discussionsupporting

confidence: 78%

The Ligands of Estrogen Receptor α Regulate Cytochrome P4502C9 (CYP2C9) Expression

Mwinyi¹,

Cavaco²,

Yurdakok³

et al. 2011

J Pharmacol Exp Ther

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“…As suggested previously (Zhang et al, 2008), up-regulation of Cyp3a41 may be attributed to the combined effects of pregnancy hormones on P450 expression. On the other hand, estrogen down-regulates human CYP2C19 expression in an ER␣-dependent manner (Mwinyi et al, 2010). These regulatory effects of hormones on P450 expression support potentially significant roles of pregnancy hormones in the reduced P450 expression during mouse pregnancy.…”

Section: Discussionmentioning

confidence: 90%

Altered Cytochrome P450 Expression in Mice during Pregnancy

Koh¹,

Xie²,

Yu³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human pregnancy is known to influence hepatic drug metabolism in a cytochrome (P450)-specific manner. However, the underlying mechanisms remain unknown, in part due to a lack of experimental models to study altered drug metabolism during pregnancy. In this study, we examined how pregnancy influences expression of major P450 isoforms in mice. Liver tissues were isolated from female FVB/N-mice at different gestational time points: prepregnancy, 7, 14, and 21 days of pregnancy, and 7 days postpartum. mRNA expression levels of major P450 isoforms (Cyp1a2, Cyp2a5, Cyp2b10, Cyp2c37, Cyp2d22, Cyp2e1, Cyp3a11, and Cyp3a41) in the liver tissues were determined by quantitative real-time polymerase chain reaction. Whereas Cyp2a5 expression was unchanged, Cyp3a41 expression was significantly increased during pregnancy. In contrast, expression of Cyp1a2, Cyp2c37, Cyp2d22, Cyp2e1, and Cyp3a11 was decreased. Expression of Cyp2d22 and Cyp2e1 isoforms correlated with that of peroxisome proliferatoractivated receptor (PPAR)␣ in the mouse livers, suggesting potential involvement of PPAR␣ in down-regulation of the P450 expression during pregnancy. Effects of pregnancy on expression of other P450 mouse isoforms as well as on in vivo drug disposition remain to be characterized. These results provide a guide for future studies on P450 regulation during pregnancy.

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“…In addition to genetic polymorphisms, endogenous and exogenous stimuli may also affect CYP2C19 expression dramatically through the mediation of transcription factors, such as the estrogen receptor α (ERα) [9], the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) which utilize the same DNA sequence binding specificity [10], the glucocorticoid receptor (GR) [10], and the GATA-4 transcription factor [11], by binding their response elements located at the CYP2C19 promoter. Drug-drug interactions affecting ethinylestradiol can down-regulate the expression of CYP2C19 through the interaction of ligand-bound ERα with its cognate estrogen response element (ERE) at position 151/−147 in the CYP2C19 promoter [9], providing a mechanism for impaired CYP2C19 expression associated with the use of oral contraceptives by women.…”

Section: Introductionmentioning

confidence: 99%

“…Drug-drug interactions affecting ethinylestradiol can down-regulate the expression of CYP2C19 through the interaction of ligand-bound ERα with its cognate estrogen response element (ERE) at position 151/−147 in the CYP2C19 promoter [9], providing a mechanism for impaired CYP2C19 expression associated with the use of oral contraceptives by women. On the other hand, the induction of CYP2C19 by rifampicin or other xenobiotics is due to ligand-dependent activation of transcription through the interaction of PXR/CAR with the CAR response element (CAR-RE) located within the proximal promoter of CYP2C19 [12], providing a mechanistic explanation for increased clearance of some CYP2C19-metabolized drugs, including warfarin [13], mephenytoin [14], and hexobarbital [15], in humans exposed to PXR/CAR agonists.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

Green

Tolleson

et al. 2015

Biochemical Pharmacology

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Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of many drugs. Extensive studies have demonstrated that genetic variants and endogenous and environmental factors play important roles in the expression of CYP2C19. However, the role of microRNAs (miRNAs) in controlling CYP2C19 expression has not been investigated completely. In the present study, we performed in silico analysis to rank putative miRNA/CYP2C19 hybrids with regards to the predicted stabilities of their duplexes and then we applied a series of biochemical and molecular assays to elucidate the underlying functional mechanisms for the regulation of CYP2C19 by miRNAs. In silico analysis indicated that hsa-miR-23a-3p and hsa-miR-29a-3p target the coding region of CYP2C19 with hybrid stabilities of −27.5 kcal/mol and −23.3 kcal/mol, respectively. RNA electrophoresis mobility shift assays showed that both hsa-miR-23a-3p and hsa-miR-29a-3p miRNAs were able to bind directly to their cognate targets in the CYP2C19 transcript. Further, a significant inverse correlation was found between chemically-induced up-regulation of hsamiR-29a-3p and CYP2C19 expression in HepaRG cells. In addition, inverse correlations were also observed in human liver tissue samples between the level of CYP2C19 mRNA expression and both hsa-miR-23a-3p and hsa-miR-29a-3p levels. All these results demonstrated the suppressing role of hsa-miR-29a-3p on CYP2C19 expression.

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Regulation of CYP2C19 Expression by Estrogen Receptor α: Implications for Estrogen-Dependent Inhibition of Drug Metabolism

Cited by 52 publications

References 35 publications

The Ligands of Estrogen Receptor α Regulate Cytochrome P4502C9 (CYP2C9) Expression

The Ligands of Estrogen Receptor α Regulate Cytochrome P4502C9 (CYP2C9) Expression

Altered Cytochrome P450 Expression in Mice during Pregnancy

MicroRNA hsa-miR-29a-3p modulates CYP2C19 in human liver cells

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