Activities of aldo-keto reductase 1 enzymes on two inhaled corticosteroids: Implications for the pharmacological effects of inhaled corticosteroids
Open accessAbstract
Inhaled corticosteroids (ICS) are a mainstay anti-inflammatory therapy for the management of asthma. ICS are synthetic glucocorticoids that are structurally similar to the natural active human glucocorticoid cortisol. Steroid transforming enzymes of the aldo-keto reductase (AKR) family, namely AKR1D1 (5β-steroid reductase) and AKR1C1-4 (ketosteroid reductases) are implicated in the systemic metabolism of cortisol in liver. In this study, the activities of these AKR1 enzymes on cortisol and two ICS compounds budesonide (BUD) and flunisolide (FLU) were investigated. It was found that the catalytic efficiency of AKR1D1 for the reduction of the double bond in cortisol was 4- and 10-fold higher than the catalytic efficiencies of AKR1D1 with FLU and BUD, respectively. This suggests that compared to cortisol, for which the 5β-reduction is a major metabolic pathway, a lower degree of systemic (hepatic) metabolism of BUD and FLU via AKR1D1 takes place. In addition, BUD potently inhibited AKR1D1 and AKR1C4, the key steroid metabolizing enzymes in liver, which may disrupt endogenous steroid hormone metabolism and thus contribute to BUD-induced systemic effects. Activities of AKR1C1-3 on cortisol and the two ICS compounds (targeting the 20-keto group) suggest these enzymes may be involved in the local (lung) metabolism of these glucocorticoids.
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AKR1D1 has broad substrate specificity, reducing C18, C19, C21 and C27 Δ4-ketosteroids and some synthetic drugs.
“AKR1D1 has broad substrate specificity; it catalyzes the reduction of C18, C19, C21 and C27 Δ4-ketosteroids and some synthetic drugs”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [24]
Budesonide and flunisolide can be metabolized by AKR1D1 and AKR1C enzymes and also act as inhibitors of AKR1 enzymes.
“The inhaled synthetic corticosteroids budesonide and flunisolide used in anti-inflammatory drug therapy in asthma patients can be metabolized by AKR1D1 and AKR1C enzymes. These steroids also act as inhibitors of AKR1 enzymes.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [24]
Budesonide is a more potent inhibitor of liver AKR1D1 and AKR1C4 than flunisolide, suggesting that this inhibition might contribute to budesonide's undesirable systemic effects.
“budesonide was a more potent inhibitor of the AKR1D1 and AKR1C4 enzymes in the liver than flunisolide suggesting that this inhibition might contribute to the undesirable systemic effects of budesonide”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [24]
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Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism
Rižner, T. L., & Penning, T. M. (2014) · Steroids · doi:10.1016/j.steroids.2013.10.012 · Cited by 217 · see citing works
- Authors
- Jin, Y.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Jin, Yi
- Venue
- Chemico-Biological Interactions
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 191
- Issue
- 1-3
- Pages
- 234-238
- ISSN
- 0009-2797 (ISSN-L)
- PMC
- PMC3100382
- OpenAlex
- W2004387902
- Cited by
- 16
- References
- 37
- Citations by year
- 2026: 1 · 2024: 3 · 2021: 2 · 2020: 1 · 2016: 1 · 2014: 2 · 2013: 3 · 2012: 2
- FWCI
- 1.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Chemico-Biological Interactions (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01-DK47015, P30 ES015857)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- aldo-keto reductase, AKR1D1, AKR1C4, inhaled corticosteroids, budesonide, flunisolide, cortisol metabolism, enzyme inhibition, hepatic steroid metabolism, asthma, glucocorticoids
- MeSH terms
- Administration, Inhalation, Adrenal Cortex Hormones, Drug Resistance, Fluocinolone Acetonide, Humans, Hydrocortisone, Oxidation-Reduction, Oxidoreductases, Budesonide
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