Emerging corticosteroid resistance: Need for customized medication based on pharmacogenomics profiling

INTRODUCTION

According to the World Health Organization’s step pyramid therapy for inflammatory diseases, corticosteroids are currently utilized to treat a wide range of inflammatory illnesses. Corticosteroids are also used to treat rheumatoid arthritis (RA), systemic lupus erythematosus, alcoholic hepatitis, asthma, chronic obstructive pulmonary disease, and other chronic inflammatory illnesses, although evidence for their usefulness in these cases is limited (Rainsford et al., 2015). Dexamethasone and other corticosteroids, such as prednisone, prednisolone, methyl prednisolone, and betamethasone, are routinely used to treat inflammatory conditions. Large interindividual variability in needs affects the usage of steroids, necessitating dose modifications to address issues such as insufficient therapeutic action or substantial side effects in patients (Liu et al., 2013). About 20%–30% of the patients treated with corticosteroids experience moderate side effects, and about 11% of them develop major side effects, such as gastrointestinal bleeding, peptic ulcers, and hypotension. Despite the lack of hard evidence, the issue of inadequate therapy even after corticosteroid use remains a significant clinical challenge (Narum et al., 2014). Genetic variables account for around 30%–70% of the interindividual variability in corticosteroid demand, according to animal studies and twin studies in humans. The variation in corticosteroid dose requirements has been linked to genetic polymorphisms in corticosteroid drug metabolizing enzymes, corticosteroid receptors, and inflammatory pathway components (Smolen et al., 2018). This review aims to highlight the detailed genetic features linked with corticosteroid resistance in order to identify variants that could be included in the application of a corticosteroid. For this review, we conducted a literature search in PubMed and Google Scholar using the following MESH terms: corticosteroids genetic polymorphism, resistance, and inflammatory illnesses. When the search was restricted to English from the beginning of February 2022, 290 articles were found.

CORTICOSTEROID RECEPTORS

The cytoplasmic glucocorticoid receptor (GR) is responsible for glucocorticoids’(GC) potential therapeutic effects. The GR could be a polymeric protein with three protein domains: the nontransactivation domain (NTD), DNA-binding domain (DBD), and ligand-binding domain (LBD) (Oakley and Cidlowski, 2013). Within the LBD and even at the DBD hinge region, two nuclear localization signals (NLSs) can be found. The NTD, which spans the GR’s amino acids 1–420, is the most stable and thus the most variable domain of all nuclear receptors. A transcription activation function is present in the NTD that stimulates target genes without the use of ligands and serves as the primary site for all transcription factors (Ramamoorthy and Cidlowski, 2016). Among all the nuclear receptor proteins, the central DBD is well-preserved. Two of its zinc finger motifs engage glucocorticoid response element (GRE) and target DNA sequences in interactions. By combining 12 helices and 4 sheets, the hydrophobic ligand-binding pocket in the LBD is created. This carboxyterminal region contains a second activation function domain and sequences required for enabling ligand-dependent factor interactions (Duma et al., 2006).

Significant progress has been made in the gene regulation by which GCs function in recent years, and thus in the concept of such interpatient variability. Instead of being self-contained, the ligand-free GR is found in a heteromeric complex with molecular chaperones and co-chaperones in the cell. The cytoplasm contains GRs as 9S heteromeric complexes with minimal DNA binding. An heat shock protein 90 (Hsp90) dimer is linked to the receptor via protein–protein interactions within the hormone-binding domain with the “core” unit of an untransformed receptor. When GC bind to the cytosolic GR, they cause it to detach from Hsp90 and transition from a DNA-binding to a non-DNA-binding state in a temperature-dependent manner because the hormone causes the GR to separate from Hsp90 in intact cells and because the GR’s interaction with Hsp90 corresponds to the hormone-inducible behavior of receptor mutants. The chaperone proteins identified in the heterocomplex include Hsp90, heat shock protein 70 (Hsp70), Hsp40, heat shock organizing protein, p23, and the immunophilins FKBP51 and FKBP.

In the biologically developed form of the heterocomplex, the free GR is attached to an Hsp90 dimer, p23, and any of the Hsp90 cochaperones besides Hsp70/Hsp90, a coordinating protein (Kirschke et al., 2014). Such interactions are necessary for maintaining the receptor’s proper folding in a hormone-responsive state. When the receptors attach to ligands, the conformational changes reveal the DBD previously buried within the ligand-free conformation (de Iudicibus et al., 2011). NLSs are a densely packed arrangement of 588 basic amino acids localized within the DBD and engage with nuclear transport factors after being detected by cytosolic receptors (importins) (Beck et al., 2009). The movement of nuclear heterocomplexes is necessary for transactivating target genes. Nucleotide-binding complexes are thought to be used in ligand- and energy-dependent ways during translocation, which is a tightly regulated process. Nuclear transport regulators from the importin-12 family control it (Pemberton and Paschal, 2005). The nuclear membrane-to-GC-bound GR translocation was previously found to be significantly regulated by importin-13 (IPO13). The DBD’s zinc finger motifs enable the functionalized receptor to interact directly with particular DNA sequences known as GC responsive elements (GREs, 5?-GGTACAnnnTGTTCT-3? where n denotes any nucleotide), which are present in the promoter region of GC responsive genes (Reddy et al., 2009).

MOLECULAR MECHANISM OF CORTICOSTEROIDS

The GR is a transcriptional regulatory factor that homodimerizes on GR and promotes regulatory coactivators to a gene promoter. The GR regulates a variety of unique gene networks, each of which is dictated by certain cellular and physiological circumstances. cAMP response element-binding, CREB binding protein, steroid receptor coactivator 1, GR interacting protein, p300, and switching/sucrose nonfermenting chromatin remodeling complex (SWI/SNF) are examples of coactivators that initiate histone acetylation and allow the transactivation of GC responsive genes (Smith et al., 1996).

Transactivation primarily boosts the transcription of genes involved in physiological activities and is therefore to blame for the majority of adverse reactions, even though some of GC’s anti-inflammatory effects are obtained by inducing anti-inflammatory genes like interleukin 10 and the inhibitor of nuclear factor kappa B (NF-κB) (Desmet and De Bosscher, 2017). Similar to how positive GREs drive transcriptional upregulation in response to GCs, negative GREs (5?-GGTACAnnnTGTTCT-3?) downregulate the reactive expression of genes. Therefore, the presence of GRs on GREs may prevent activator protein 1 (AP1) and NF-κB from binding to the same promoter regions or transactivating their respective inhibitory proteins. With the AP1, NF-κB, and transcription signal transducers and activators, the GRs physically interact. The majority of GC’s anti-inflammatory effects are believed to be caused by transrepression (Xavier et al., 2016). Exogenous (therapeutic) GC differ from endogenous (physiologic) GC in several aspects; the most significant are their mineralocorticoid and glucocorticoid (anti-inflammatory) effects (Buttgereit et al., 2011) (Table 1). Philip S. Hench was the first to use biological cortisone to effectively treat people with atrophic arthritis in 1948 (Lipworth, 1999). In less than a year, Hench became aware of cortisone’s mineralocorticoid-related side effects, such as sodium/water retention and potassium loss. As a result, throughout the 1950s and 1960s, novel therapeutic GC were produced. These medicines varied from the cortisone reported by Hench in that they had a lower mineralocorticoid action but much higher glucocorticoid active compounds (Samuel et al., 2017). Prednisone/prednisolone, methylprednisolone, and fluorinated GC like dexamethasone and betamethasone are among the most well tolerated and widely utilized of these medicines. Other differences between synthetic medications and natural GC include plasma dynamics, metabolism, biologic half-life, lipophilicity, and drug–receptor interactions (Kemp et al., 2016).

INTERINDIVIDUAL VARIABILITY OF CORTICOSTEROIDS

Individual variability in glucocorticoid receptivity is a significant barrier to glucocorticoid clinical applications, with up to 30% of the population displaying glucocorticoid resistance. According to developments in glucocorticoid expression patterns, impaired glucocorticoid response can be caused by increased expression of the glucocorticoid receptor β (GRB) and glucocorticoid receptor α (GRA) D isoforms, differences in GR phosphorylation, and homologously reduced the expression of GRs. Animal models with a similar pathophysiology to the human disease process under investigation must conduct preclinical investigations and novel drug tests efficiently. The effect of the GCs’ genome has been studied in a variety of animal species. More than 95% of the human genome is shared by chimps, and they can be genetically changed to resemble specific human diseases. Additionally, it is possible to conduct trials that would be challenging on humans, while taking into account human variability (Bryda, 2013). The extent to which nonhuman models mimic human pathophysiology is unknown, despite the fact that glucocorticoid treatment in mouse models replicates some of the findings reported in humans (Hardy et al., 2018).

CORTICOSTEROIDS’ BIOTRANSFORMATION

Corticosteroid metabolism is influenced by genetics. The genetic diversity seen in critical proteins along the route has a direct impact on a person’s ability to metabolize drugs (Miller and Auchus, 2011). The cytochrome P450 (CYP) 3A enzyme family is responsible for the metabolism of GC like betamethasone (BMZ) and dexamethasone. One of the most commonly used inhaled GC for treating asthma is fluticasone propionate (FP), a trifluorinated synthetic glucocorticoid (Mager et al., 2003). This drug has a significant immunosuppressive effect, as demonstrated by the whole-blood lymphocyte proliferation assay. The metabolic biotransformation of FP, which is largely attributed to the CYP 3A enzymes CYP3A4, CYP3A5, and CYP3A7, ends the biological effects of FP. The most prevalent CYP3A isoform in the human lung is CYP3A5, but CYP3A4—possibly the most significant hepatic 3A enzyme—is only found in certain tissues. In the past, it has been demonstrated that substances can reduce the production of CYP3A4 in human lungs by binding to upstream gene regulatory domains of the CYP3A4 gene (Stockmann et al., 2013). CYP3A7, which was initially discovered to be expressed at low but detectable levels in lung samples from adults up to age 35, is possibly the most prevalent type of CYP3A expressed in the human fetal liver. Based on the upregulation of CYP3A5 and CYP3A7 in the bronchial mucosa and pulmonary parenchyma, our results suggest that these two enzymes are in charge of the local metabolization of FP in the lungs (Mager et al., 2003). Alterations in these CYP3A enzymes, which regulate corticosteroid biotransformation in vivo, could explain some of the variations in corticosteroid responses. The drug oxidation phenotypes of CYP3A4 are diverse yet consistently distributed. Nonetheless, there is significant proof of inheritance. In initial twin studies, the rate of antipyrine 4-hydroxylation, which is catalyzed predominantly by CYP3A4, was extremely hereditary (85%) (Klein and Zanger, 2013). A recurrent drug administration technique also indicated a high degree of inheritance for CYP3A4 drug oxidation capability for several of its targets (erythromycin: 89% and midazolam: 96%) (Teng, 2015).

A recent study identified the hereditary versus nongenetic influence on differential CYP3A4 induction using a traditional twin model technique. Although uninduced levels were not examined, it was reported that provoked CYP3A4 activity was about 66%, and that at least 20% of the variability was accounted for by environmental factors like BMI, alcohol consumption, and smoking habit/quantity (Rahmioglu et al., 2014). The CYP 3A enzyme breaks down prednisolone. Although CYP3A5 has a lower activity than CYP3A4, the two proteins have identical catalytic specificities (Floyd et al., 2003). The A6986G nucleotide polymorphism (SNP) inside intron 3 of CYP3A5, which is termed CYP3A5*3, correlates with CYP3A5 expression levels. The CYP3A5*3 mutant allele may also contribute to prednisolone pharmacokinetic variations between individuals (Zanger and Schwab, 2013).

Another possibly important gene is MDR1 (ABCB1), which codes for the transmembrane transporter p glycoprotein (Pg). The gene is involved in the metabolism of numerous xenobiotics and has been examined in relation to the susceptibility to Chron’s disease (including steroids) (Table 2).

Numerous studies have focused on the two SNPs in the gene, C3435T (rs1045642), a synonymous SNP, and G2677T/A, a nonsynonymous triallelic variant (Krupoves et al., 2011). Researchers thought that IPO13 was a good biologic candidate gene for pharmacogenetics response to glucocorticoid therapy for asthma because of its established capacity to influence anti-inflammatory GC actions (especially in airway epithelium). To determine whether 10 common IPO13 DNA sequence variants affected the clinical outcome of inhaled corticosteroids (including budesonide, a commonly prescribed inhaled GC), researchers genotyped a group of asthmatic adolescents taking part in a clinical trial examining the long-term efficacy of inhaled anti-inflammatory therapy (Song et al., 2017) (Table 3).

PHARMACODYNAMICS

Due to increased secretion of the adrenocorticotrophic hormone (ACTH), mutations in the GR receptor cause disruption of hypothalamic–pituitary–adrenal (HPA) axis feedback mechanisms (reduced) and impaired function, leading to increased cortisol and mineralocorticoid output by the adrenal gland. On the other hand, if the GR gene is mutated, the cell would be more vulnerable to GC’s actions. The mechanisms that determine a cell’s susceptibility and resistance to GCs have remained unclear until now. In previous investigations, various polymorphisms in the GR gene have been associated with generalized sensitivity disorders. Single nucleotide polymorphisms (SNPs) in the GR pathway have been connected to therapeutic differences in corticosteroid response in a variety of inflammatory diseases. There is no proof, as far as researchers are aware, that SNP variations have an impact on pharmacogenetic end points (Kostik et al., 2011).

Glucocorticoid receptor

The GR, a member of the nuclear hormone receptor family of ligand-activated transcriptional activity, is the main target of GCs. The GR controls the transactivation or repression of GC-sensitive genes through protein interactions with other transcriptional regulators or direct DNA binding. The amplitude and effectiveness of the GC activity are influenced by the GR’s characteristics. In Figure 1, the genetic variations in the GR are related to the reported GC reactivity heterogeneity. A binding assay was used to examine GCR expression in RA patients, mainly in peripheral mononuclear cells (Olsen et al., 2004).

Table 1. Salient molecular biological features of important genes involved in corticosteroid resistance. [Click here to view]

Table 2. Salient molecular biological features of important SNPs involved in corticosteroid resistance. [Click here to view]

It has been shown that GCR expression is downregulated in RA. Clinical evidence of steroid effect diminution, with long-term glucocorticoid medication, is uncommon, as the effect varies from patient to patient. Exon 9beta (rs6198), TthIII1 (rs10052957), and ER22/23EK (rs6189&6190) polymorphisms in the GR gene have all been associated with varied degrees of resistance to exogenous GCs in patients with a variety of inflammatory diseases (Table 2).

Table 3. Genetic polymorphism associated with corticosteroid resistance and its effects. [Click here to view]

Figure 1. Molecular mechanism of corticosteroids. [Click here to view]

Exon 2 of the GR gene contains the ER22/23EK polymorphism, which is located in the transcriptional region between codons 22 and 23. The particular sequence mutation is GAG AGG to GAA AAG, which translates glutamic acid arginine (ER) rs6189 to glutamic acid lysine (EK) rs6190. In prior investigations, the ER22/23 EK polymorphism was connected to GCs’ resistance. The polymorphism ER22/23EK is linked to a reduced sensitivity to GCs. As a result, GRA performs better at translating than GRB, with the latter having a higher transactivating effect during transient transfection (El-Fayoumi et al., 2018). According to COS1 cell studies, the GC sensitivity of GR (ER22/23EK) carriers was reduced (Russcher et al., 2005). According to an in vivo study, ER22/23EK carriers have better metabolic health profiles in cardiovascular patients and a higher survival rate after receiving 1md DEX than noncarriers. They are also more “cortisol-resistant’ than noncarriers.

A mutation known as Tth111I (rs10052957) has been found in the NR3C1 gene promoter. The SNP is located 3,807 bp above the exon’s primary transcription start point in a 27-kb intron upstream of the transcription initiation site (between exons Ex1C and Ex1H) (Nicolaides et al., 2010). The gene promoter undergoes a C > T alteration as a result. In individuals with nephritic syndrome, NR3C1 rs10052957 revealed a little difference in steroid resistance between bearers of the A allele and the G allele (Liu et al., 2018). The Tth111I polymorphism dramatically altered the effect of corticosteroids on psychiatric outcomes in heart surgery patients after dexamethasone administration (Kok et al., 2018).

The 9beta (rs6198) SNP, an adenine to guanine nucleotide substitution in the GR gene, is located in the GR9 region. The G allele of this polymorphism results in a more stable GR9 mRNA and increased GR9 isoform receptor protein synthesis, which may be related to GC resistance, according to in vitro findings (Castro-Vale et al., 2021). An ATTTA pattern symbolizes the shift from A to G in the nucleotide (to GTTTA). The ATTTA motif is considered to interfere with mRNA and restrict the in vitro synthesis of receptor proteins. It has been discovered that the GR9beta transcript variation is a dominant-negative GR inhibitor. According to in vitro research, the GR9beta polymorphism increases sustained GR mRNA levels and may also increase GC resistance. Furthermore, GR9beta has been associated to increased vulnerability to RA and decreased resistance to Staphylococcus aureus nasal colonization, suggesting an immune system function mediated by GR (Van Winsen et al., 2009). In certain inflammatory disorders, the increased expression of the GR9 protein variation has been linked to GC resistance.

A recent study found that healthy male carriers of the 9beta variation exhibited higher overall cortisol responses following social stress and higher ACTH levels after a dexamethasone suppression test (0.25 mg), suggesting GC insensitivity at the level of the HPA axis. The involvement of the polymorphisms ER22/23EK (rs6189, rs6190), Tth111I (rs10052957), and GR beta 9 (rs6198) in responding to corticosteroids in a number of illnesses has not received much attention. A Tth111I polymorphism in the NR3C1 gene was found to be connected to the pathophysiology of chronic bronchitis, which causes asthma. On the other hand, alterations of GC sensitivity by 9 and ER22/23EK may be linked to variations in the clinical response to GCs in individuals with RA or other inflammatory disorders (Pratt et al., 1992). The ER22/23EK polymorphism, one of the three polymorphisms previously discussed, has been associated by numerous researchers with corticosteroid resistance in the majority of inflammatory illnesses.

CONCLUSION

In medical practice, GCs are the most commonly used treatment for a variety of illnesses, including immunosuppressive and anti-inflammatory medications. The effects of GCs are mediated by a plethora of nongenomic and genomic pathways, most notably gene transcription control. By interacting with the GR, GCs control the transcription of some target genes. In the scoping research, we aimed to characterize the key genes and SNPs that may cause glucocorticoid resistance and the molecular mechanisms of anti-inflammatory effects, which could be useful in creating newer pharmaceutical alternatives for undoing GC resistance.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.

FINANCIAL SUPPORT

There is no funding to report.

CONFLICTS OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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