Mechanisms involved in the side effects of glucocorticoids
Introduction
Since the successful use of hydrocortisone (cortisol), the principal glucocorticoid (GC) of the human adrenal cortex, in 1948 in the suppression of the clinical manifestations of rheumatoid arthritis, numerous compounds with GC activity have been synthesized. Today, they represent the standard therapy for reducing inflammation and immune activation in asthma, as well as allergic, rheumatoid, collagen, vascular, dermatological, inflammatory bowel, and other systemic diseases, and in allotransplantation. The therapeutic usage of GCs has risen continuously in recent years. In Germany, ∼6.6 million prescriptions were written in 1995 (Schwabe, 1996) and ∼10 million new prescriptions are written just for oral corticosteroids each year in the United States. Overall, the total market size is considered to reach ∼10 billion US dollars per year. GCs are used in almost all medical specialties for systemic therapies, as well as topical therapy. Apart from application to the skin, the latter includes the respiratory route for asthma and via the gut for inflammatory bowel diseases.
GCs are 21-carbon steroid hormones. The clinical potency of the various synthetic steroids depends on the rate of absorption, the concentration in the target tissues, the affinity for the steroid receptor, and the rate of metabolism and subsequent clearance. The plasma half-life ranges between 80 (cortisol) and 270 (dexamethasone) min. Approximately 90% of endogenous circulating cortisol is bound with high affinity to the plasma protein corticosteroid-binding globulin. Most synthetic steroids, with the exception of prednisolone, however, have low affinity for the corticosteroid-binding globulin and are bound predominantly to albumin. Only the small fraction of circulating corticosteroids that are not protein-bound are free to exert biological action, whereas those associated with proteins are protected from metabolic degradation. GCs are metabolized in the liver. The kidney excretes 95% of the conjugated metabolites, and the remainder are lost in the gut (Goodwin, 1994).
The biological effects of GCs are mediated via the GC receptor (GR). The relevant molecular mechanisms are described in detail in Section 1.2. The resulting biological effects can be summarized as anti-inflammatory/immunosuppressive, metabolic, and toxic. The anti-inflammatory and immunosuppressive GC effects include changes in the circulation/migration of leukocytes (e.g., neutrophilia, lymphopenia, and monocytopenia) and alterations in specific cellular functions (e.g., inhibition of lymphokine synthesis, monocyte function) (Winkelstein, 1994). Whereas the anti-inflammatory and immunosuppressive effects are usually desired (Winkelstein, 1994), the metabolic and toxic effects are usually undesired. Exceptions are the use of GCs for substitution (e.g., in the case of suprarenal insufficiency—Addison's disease) or in tumor therapy (e.g., for breast cancer and plasmocytoma) (Ihle et al., 1989).
In dermatology, GCs are the most widely used therapy. The introduction of topical hydrocortisone in the early 1950s represented a great advance over previously available therapies, but it was the first of the halogenated GCs, triamcinolone acetonide, that started a revolution, cumulating in the appearance of the very potent agents available now. The enthusiasm for these highly effective agents was at its peak during the 1960s and 1970s, and perhaps inevitably, the more potent GCs were often used inappropriately and indiscriminately. Adverse effects became apparent, and the subsequent backlash of opinion against topical GCs has created confusion and prejudice against all steroid-containing preparations. In its extreme form as “steroid phobia,” it is still of considerable concern today (Maibach & Surber, 1992). Recently, a questionnaire-based study of 200 dermatology outpatients with atopic eczema assessed the prevalence of topical GC phobia in Great Britain. Overall, 72.5% of those questioned worried about using topical GCs on their own or their child's skin. Twenty-four percent of the people admitted to having been non-compliant with topical corticosteroid treatment because of these worries. The most frequent cause for concern was the perceived risk of skin thinning (34.5%). In addition, 9.5% of the patients worried about systemic absorption, leading to effects on growth and development. This indicates that a considerable number of patients today do worry about using their prescribed GCs (Charman et al., 2000).
Duration, dosage, and dosing regime and choice of the appropriate GC (a classification has been established based on their potency) and its mode of application depend on the clinical situation and take account of the risk/benefit ratio. These factors, together with an individual susceptibility of unknown reason, determine the occurrence and severity of the adverse effects (Goodwin, 1994). Overall, it can be stated that prolonged application is a high-risk factor, whereas total dose is of secondary importance. Side effects are usually more severe after systemic than after topical application. Even topical therapy, however, can induce not only local, but also systemic adverse effects, as observed after cutaneous therapy for inflammatory dermatoses (Robertson & Maibach, 1982) and pulmonary therapy for asthma (Mygind & Dahl, 1996). The side effects (summarized in Table 1) occur with different prevalence, in different organs, and after different durations of therapy. The severity ranges from more cosmetic aspects (e.g., teleangiectasia, hypertrichosis) to serious disabling and even life threatening situations (e.g., gastric hemorrhage) (Goodwin, 1994). Single or multiple side effects can occur. A typical combination is evident in the case of Cushing's syndrome, characterized by a moon face, buffalo hump, central obesity, hirsutism, osteoporosis, growth retardation, and glucose intolerance (Fig. 1).
Taken together, the side effects of GC therapy are the limiting factor for the use of these valuable agents today. Thus, there is a strong need to develop substances with the anti-inflammatory potency of classical GCs, but with reduced side effects compared with the common GCs. The basis for the development of such new compounds is a deeper understanding of the molecular and cellular actions of GCs.
The effects of GCs are mediated by two distinct nuclear receptors, the GR and the mineralocorticoid receptor (MR). The MR binds GCs with a higher affinity than the GR. While the GR is widely expressed in most cell types of the organism, the expression of the MR is restricted to epithelial cells in the kidney, colon, and salivary glands and non-epithelial cells in the brain and heart (Reichardt & Schütz, 1998). Activation of the MR leads to Na+ retention via an increased activity of epithelial Na+ channels (EnaCs), and subsequently induces an increase in blood pressure (Lifton et al., 2001). Modern synthetic GCs, however, are GR-selective.
The GR is a ligand-activated transcription factor. In the absence of the ligand, the receptor is localized in the cytoplasm as a protein complex together with heat shock proteins (HSPs)-90, p60/Hop, HSP-70, and HSP-40 and other chaperone molecules Dittmar & Pratt, 1997, Schneikert et al., 1999. Upon ligand binding, the complex dissociates and the receptor translocates into the nucleus and binds as a homodimer to regulatory elements in promoter regions of GC-responsive genes, resulting in a modulated gene transcription.
Different modes of transcription regulation by the GR-ligand complex have been described. The positive regulation of target genes is mediated by a specific binding of the activated GR-DNA to GC-response elements (GREs) in the promoter or enhancer region of responsive genes (Beato et al., 1989), followed by an induction or increase of gene transcription (Fig. 2A). This transactivation mechanism has been identified in a large variety of genes, including those encoding the gluconeogenic enzymes tyrosine aminotransferase (TAT) (Hargrove & Granner, 1985) and phosphoenolpyruvate carboxykinase (PEPCK) (Ruppert et al., 1990). The negative regulation by the GR is more variable. Firstly, the activated GR can bind to negative GREs, leading to a repression of gene transcription, possibly due to interference with the binding of essential transcription factors (Fig. 2B). This mechanism was described for the regulation of the osteocalcin Stromstedt et al., 1991, Meyer et al., 1997 and pro-opiomelanocortin (POMC) gene promoters (Drouin et al., 1993). Secondly, the GR may interact via protein-protein interaction with other transcription factors, e.g., activator protein (AP)-1, nuclear factor-κB (NF-κB), Smad3, preventing an activation of transcription by these factors (Fig. 2C) Schüle et al., 1990, Tuckermann et al., 1999, De Bosscher et al., 2000. In this case, the gene expression is controlled by the GR without binding to DNA.
When the full-length cDNA of the human GR was obtained (Hollenberg et al., 1985), two forms of the human GR were described: a steroid-binding form of 777 residues (GRα) and a non-steroid-binding truncated form of 742 residues, which differed in the 15 C-terminal residues (GRβ). The human GRβ does not bind GCs or anti-GCs, and is transcriptionally inactive on GRE-containing enhancers Hollenberg et al., 1985, Giguere et al., 1986, Oakly et al., 1996, Vottero & Chrousos, 1999. There is some controversy concerning the relative levels of GR isoforms, as well as the putative function of the GRβ isoform, and whether or not it acts as a dominant negative modulator of the GRα isoform (Carlstedt-Duke, 1999). In the peripheral blood of patients with GC-resistant asthma, however, significantly higher numbers of human GRβ positive cells were found, suggesting such a dominant negative function of the human GRβ (Leung et al., 1997). The first evidence for a physiologic role of the GRβ isoform in neutrophils was described recently by Strickland and co-workers (2001). They compared the GC sensitivity of human neutrophils and peripheral blood mononuclear cells and observed the existence of GRα/GRβ heterodimers in neutrophils only. They also demonstrated that the transfection of neutrophils from mice with a functional human GRβ, in whom no GRβ isoform has been identified (Otto et al., 1997), leads to an inhibition of GC-induced apoptosis. In T-cells, it is thought that cell death is mediated through GRα homodimers acting on GREs of GC-sensitive genes. A similar mechanism of GC-induced apoptosis is assumed for neutrophils. This suggests that the GRα/GRβ heterodimers in human neutrophils are functionally inactive, but that their expression might limit the responsiveness towards GC effects mediated via the GRα homodimer.
Section snippets
Mechanisms of glucocorticoid receptor-mediated therapeutic effects
The general molecular mechanisms after GR binding have been described in the previous section. The therapeutic, anti-inflammatory, and immunosuppressive effects of the GR/ligand complex are mediated by transrepression and by transactivation, as well as by other mechanisms that may affect several signal transduction pathways. Genes that code for anti-inflammatory proteins are induced by the GR via a GR-DNA interaction. Thus, the expression of, e.g., lipocortin-1, interleukin (IL)-1 receptor
Skin
Topical, as well as systemic, GC therapy can induce numerous cutaneous side effects. The potency and in particular the duration of therapy determine their occurrence and severity. The most important side effects include atrophy of the epidermis and the dermis (Fig. 3B), or even the subcutis, which can result in the irreversible striae rubrae distensae (Fig. 3A), and disturbed wound healing. A less, but not unimportant, side effect is the hypertrichosis (enhanced hair growth), which facially
Summary/conclusion
GC-mediated effects are very complex and tightly controlled. This strong control is necessary to ensure the survival of the organism under several conditions, such as stress, infections, etc. With the development of new techniques in molecular biology, biochemistry, and cell biology, considerable progress has been achieved in the discovery of the molecular mechanisms that mediate the GC effects. Research efforts, however, were focussed mainly on the desired GC effects, their anti-inflammatory
Acknowledgements
We would like to thank Professor Andrew Cato (Forschungszentrum Karlsruhe, Germany) and Professor Guenther Schuetz (DKFZ, Heldelberg, Germany) and Dr. Christoph Niels (University Marburg, Germany) for critical reading of the manuscript, Professor Stephen Katz (NIH, Bethesda, USA) for helpful discussions, Professor Wolfram Sterry (Charite, Berlin, Germany) for providing the clinical figures (Figs. 3A–D and Fig. 1, rerpectively), and Stefanie Schoepe for editing the manuscript.
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