The constitutive androstane receptor and pregnane X receptor in the brain

doi:10.1111/bph.15055

Review

. 2020 Jun;177(12):2666-2682.

doi: 10.1111/bph.15055. Epub 2020 Apr 22.

The constitutive androstane receptor and pregnane X receptor in the brain

Pablo Torres-Vergara^{1

2

3}, Yu Siong Ho⁴, Francisca Espinoza², Francisco Nualart², Carlos Escudero^{5

3}, Jeffrey Penny⁴

Affiliations

¹ Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile.
² Centro de Microscopía Avanzada, CMA-BIO BIO, Laboratorio de Neurobiología y Células Madres NeuroCellT, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
³ Group of Research and Innovation in Vascular Health (GRIVAS Health), Universidad del Bío Bío, Chillán, Chile.
⁴ Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Health and Medicine, The University of Manchester, Manchester, UK.
⁵ Laboratorio de FisiologíaVascular, Departamento de Ciencias Básicas, Facultad de Ciencias Básicas, Universidad del Bío-Bío, Chillán, Chile.

PMID: 32201941
PMCID: PMC7236070
DOI: 10.1111/bph.15055

Review

The constitutive androstane receptor and pregnane X receptor in the brain

Pablo Torres-Vergara et al. Br J Pharmacol. 2020 Jun.

. 2020 Jun;177(12):2666-2682.

doi: 10.1111/bph.15055. Epub 2020 Apr 22.

Authors

Pablo Torres-Vergara^{1

2

3}, Yu Siong Ho⁴, Francisca Espinoza², Francisco Nualart², Carlos Escudero^{5

3}, Jeffrey Penny⁴

Affiliations

¹ Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Concepción, Chile.
² Centro de Microscopía Avanzada, CMA-BIO BIO, Laboratorio de Neurobiología y Células Madres NeuroCellT, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile.
³ Group of Research and Innovation in Vascular Health (GRIVAS Health), Universidad del Bío Bío, Chillán, Chile.
⁴ Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Health and Medicine, The University of Manchester, Manchester, UK.
⁵ Laboratorio de FisiologíaVascular, Departamento de Ciencias Básicas, Facultad de Ciencias Básicas, Universidad del Bío-Bío, Chillán, Chile.

PMID: 32201941
PMCID: PMC7236070
DOI: 10.1111/bph.15055

Abstract

Since their discovery, the orphan nuclear receptors constitutive androstane receptor (CAR;NR1I3) and pregnane X receptor (PXR;NR1I2) have been regarded as master regulators of drug disposition and detoxification mechanisms. They regulate the metabolism and transport of endogenous mediators and xenobiotics in organs including the liver, intestine and brain. However, with proposals of new physiological functions for NR1I3 and NR1I2, there is increasing interest in the role of these receptors in influencing brain function. This review will summarise key findings regarding the expression and function of NR1I3 and NR1I2 in the brain, hereby highlighting the need for further research in this field.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**FIGURE 1**
Known biological actions of NR1I3 (CAR) and NR1I2 (PXR). Since both nuclear receptors are ubiquitously expressed in organs and tissues of mammalians, they regulate the expression of proteins involved in metabolism and transport of nutrients, endogenous mediators and xenobiotics in a tissue‐dependent manner. Furthermore, NR1I3 and NR1I2 can also influence biological processes including inflammation and apoptosis through protein‐protein interactions. Recent research have demonstrated that in the brain, apart from their role in some of the above‐mentioned processes, NR1I3 and NR1I2 may participate in complex functions such as behaviour

**FIGURE 2**
Comparison of the downstream events of the NR1I3 (CAR) and NR1I2 (PXR) signalling pathways in liver and brain. Most of the research aiming to characterise the signalling pathways of NR1I3 and NR1I2 has been conducted in liver, whilst organs such as the brain are much less studied. This issue is particularly important as brain endothelial cells and neurons express both receptors and the response to the ligand‐based activation of NR1I3 and NR1I2 appears vary amongst areas of the brain. This outcome is consistent with the tissue‐dependent effects of

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References

1. Abass, K. , Lamsa, V. , Reponen, P. , Kublbeck, J. , Honkakoski, P. , Mattila, S. , … Hakkola, J. (2012). Characterization of human cytochrome P450 induction by pesticides. Toxicology, 294, 17–26. 10.1016/j.tox.2012.01.010 - DOI - PubMed
1. Aleksunes, L. M. , & Klaassen, C. D. (2012). Coordinated regulation of hepatic phase I and II drug‐metabolizing genes and transporters using AhR‐, CAR‐, PXR‐, PPARα‐, and Nrf2‐null mice. Drug Metabolism and Disposition, 40, 1366–1379. 10.1124/dmd.112.045112 - DOI - PMC - PubMed
1. Alexander, S. P. H. , Cidlowski, J. A. , Kelly, E. , Mathie, A. , Peters, J. A. , … GTP colaborators . (2019). The concise guide to pharmacology 2019/2020: Nuclear hormones receptors. British Journal of Pharmacology, 176, S229–S246. 10.1111/bph.14748 - DOI - PMC - PubMed
1. Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. … CGTP collaborators (2019). The concise guide to pharmacology 2019/20: Enzymes. British Journal of Pharmacology, 176, S297–S396. 10.1111/bph.14572 - DOI - PMC - PubMed
1. Alexander, S. P. H. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , … GTP collaborators . (2019). The concise guide to pharmacology 2019/20: Transporters. British Journal of Pharmacology, 176, S397–S493. 10.1111/bph.14753 - DOI - PMC - PubMed

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[1] Abass, K. , Lamsa, V. , Reponen, P. , Kublbeck, J. , Honkakoski, P. , Mattila, S. , … Hakkola, J. (2012). Characterization of human cytochrome P450 induction by pesticides. Toxicology, 294, 17–26. 10.1016/j.tox.2012.01.010 - DOI - PubMed

[2] Abass, K. , Lamsa, V. , Reponen, P. , Kublbeck, J. , Honkakoski, P. , Mattila, S. , … Hakkola, J. (2012). Characterization of human cytochrome P450 induction by pesticides. Toxicology, 294, 17–26. 10.1016/j.tox.2012.01.010 - DOI - PubMed

[3] Aleksunes, L. M. , & Klaassen, C. D. (2012). Coordinated regulation of hepatic phase I and II drug‐metabolizing genes and transporters using AhR‐, CAR‐, PXR‐, PPARα‐, and Nrf2‐null mice. Drug Metabolism and Disposition, 40, 1366–1379. 10.1124/dmd.112.045112 - DOI - PMC - PubMed

[4] Aleksunes, L. M. , & Klaassen, C. D. (2012). Coordinated regulation of hepatic phase I and II drug‐metabolizing genes and transporters using AhR‐, CAR‐, PXR‐, PPARα‐, and Nrf2‐null mice. Drug Metabolism and Disposition, 40, 1366–1379. 10.1124/dmd.112.045112 - DOI - PMC - PubMed

[5] Alexander, S. P. H. , Cidlowski, J. A. , Kelly, E. , Mathie, A. , Peters, J. A. , … GTP colaborators . (2019). The concise guide to pharmacology 2019/2020: Nuclear hormones receptors. British Journal of Pharmacology, 176, S229–S246. 10.1111/bph.14748 - DOI - PMC - PubMed

[6] Alexander, S. P. H. , Cidlowski, J. A. , Kelly, E. , Mathie, A. , Peters, J. A. , … GTP colaborators . (2019). The concise guide to pharmacology 2019/2020: Nuclear hormones receptors. British Journal of Pharmacology, 176, S229–S246. 10.1111/bph.14748 - DOI - PMC - PubMed

[7] Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. … CGTP collaborators (2019). The concise guide to pharmacology 2019/20: Enzymes. British Journal of Pharmacology, 176, S297–S396. 10.1111/bph.14572 - DOI - PMC - PubMed

[8] Alexander, S. P. H. , Fabbro, D. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. … CGTP collaborators (2019). The concise guide to pharmacology 2019/20: Enzymes. British Journal of Pharmacology, 176, S297–S396. 10.1111/bph.14572 - DOI - PMC - PubMed

[9] Alexander, S. P. H. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , … GTP collaborators . (2019). The concise guide to pharmacology 2019/20: Transporters. British Journal of Pharmacology, 176, S397–S493. 10.1111/bph.14753 - DOI - PMC - PubMed

[10] Alexander, S. P. H. , Kelly, E. , Mathie, A. , Peters, J. A. , Veale, E. L. , Armstrong, J. F. , … GTP collaborators . (2019). The concise guide to pharmacology 2019/20: Transporters. British Journal of Pharmacology, 176, S397–S493. 10.1111/bph.14753 - DOI - PMC - PubMed

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The constitutive androstane receptor and pregnane X receptor in the brain

Affiliations

The constitutive androstane receptor and pregnane X receptor in the brain

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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Cited by

References

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