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The ATP-binding cassette proteins ABCB1 and ABCC1 as modulators of glucocorticoid action

Nature Reviews Endocrinology volume 19, pages 112–124 (2023)Cite this article

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Abstract

Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations is well established for glucocorticoid and other lipophilic hormones; moreover, transmembrane transporters have proven critical in determining tissue responses to thyroid hormones. However, there has been less consideration of the role of transmembrane transport for steroid hormones. ATP-binding cassette (ABC) proteins were first shown to influence the accumulation of glucocorticoids in cells almost three decades ago, but observations over the past 10 years suggest that differential transport propensities of both exogenous and endogenous glucocorticoids by ABCB1 and ABCC1 transporters provide a mechanism whereby different tissues are preferentially sensitive to different steroids. This Review summarizes this evidence and the new insights provided for the physiology and pharmacology of glucocorticoid action, including new approaches to glucocorticoid replacement.

Key points

  • Humans have two circulating glucocorticoid hormones, cortisol and corticosterone, which diffuse into cells to become transcription factors when bound to their intracellular receptors.

  • The availability of glucocorticoids to interact with their receptors depends not only on their plasma concentration but also on their intracellular concentration, which is modulated by intracellular enzymes and by transmembrane transporters.

  • Glucocorticoids are susceptible to cellular export by membrane transporters from the ABC (ATP-binding cassette) transporter family: cortisol is a substrate for the ABCB1 transporter, and corticosterone for ABCC1.

  • Tissues expressing ABCB1 (such as the brain) might be relatively sensitive to corticosterone over cortisol; those expressing ABCC1, such as adipose, might be more sensitive to cortisol.

  • In future, therapeutic glucocorticoids could be selected on the basis of lower tendency to be exported from sites of efficacy and higher tendency for export from sites where harmful adverse effects occur.

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Fig. 1: Action and structure of ABCB1 and ABCC1.
Fig. 2: Tissue-specific expression of ABCB1 and ABCC1.
Fig. 3: Tissue ABC transporter expression determines glucocorticoid sensitivity.
Fig. 4: Intracellular glucocorticoid regulatory pathways.
Fig. 5: Modulation of the hypothalamic–pituitary–adrenal (HPA) axis by ABCB1 and ABCC1.

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Acknowledgements

The authors’ research on ABC transporters has been funded by the Wellcome Trust and British Heart Foundation.

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Authors and Affiliations

  1. BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

    Kerri Devine, Elisa Villalobos, Catriona J. Kyle, Ruth Andrew, Rebecca M. Reynolds, Roland H. Stimson, Mark Nixon & Brian R. Walker

  2. Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK

    Kerri Devine & Brian R. Walker

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Contributions

K.D., E.V. and M.N. researched data for the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. K.D., E.V., M.N. and B.R.W. wrote the article.

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Correspondence to Brian R. Walker.

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Nature Reviews Endocrinology thanks Tomoshige Kino, Edo de Kloet and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

The Human Protein Atlas: https://www.proteinatlas.org/

Glossary

Sanctuary sites

Areas within the body that are relatively well protected from access by drugs (for example, anticancer agents) and toxins.

α-Helices

Secondary protein structures formed by hydrogen bonding between the amine and carbonyl groups of amino acids located four residues apart, resulting in a helical structure with a tightly coiled central backbone, with side chains extending outwards.

Luminal surfaces

The lining surfaces of body channels, such as the intestines or blood vessels.

Polyspecificity

The capacity to bind multiple unrelated substrates.

Glutathione coupling

Conjugation with the tripeptide glutathione.

Phase II hepatic metabolites

Endogenous and xenobiotic compounds conjugated with glutathione, glucuronide and sulfate in the liver to improve their water solubility and thus facilitate excretion.

Syncytiotrophoblasts

Cells forming the outer layer of the placenta, and the major site of gas and nutrient exchange between mother and fetus.

Cytotrophoblasts

The inner stem cell layer of the placenta villi — cellular precursors to syncytiotrophoblasts.

Adopted orphan receptors

An orphan receptor is a receptor whose ligand has not been identified; it can later be termed an ‘adopted orphan receptor’ when a ligand is discovered.

Compound heterozygosity

The presence of two different mutant alleles at a genetic locus.

Lymphoblastoid cell lines

Immortalized cells that are derived from, and closely resemble, peripheral blood lymphocytes.

Synonymous

A silent genetic mutation in which a change in DNA sequence does not result in a change in the amino acid sequence of the protein produced.

Therapeutic index

The margin between the desirable and undesirable effects of a drug; the narrower the margin, the more likely it is that adverse effects will occur at a therapeutic dose.

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Devine, K., Villalobos, E., Kyle, C.J. et al. The ATP-binding cassette proteins ABCB1 and ABCC1 as modulators of glucocorticoid action. Nat Rev Endocrinol 19, 112–124 (2023). https://doi.org/10.1038/s41574-022-00745-9

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