Glucocorticoids Drug Metabolism

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The Role of Glucocorticoid Receptor in the Regulation of Drug Metabolism


Glucocorticoids are extremely important in our life due to their pivotal roles in maintaining homeostasis and coping with stress. Tremendous attention has focused on glucocorticoids because of their wide usage in the treatment of autoimmune and inflammatory diseases and their implications to the pathogenesis of many wide-spread disorders, such as hypertension, diabetes, obesity, etc. Many pathophysilogical effects of glucocorticoids are contributed by their transcriptional regulation of approximately 10% of our genes (Buckingham, 2006) and these effects are predominantly dependent on the interaction between glucocorticoids and the glucocorticoid receptor (GR), a ligand-activated transcription factor.

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Although a variety of physiological functions, such as immune response, metabolism, growth, etc, could be closely related to the GR-mediated gene regulation, this review will mainly focus on the GR-mediated enzyme regulation and its crucial role on drug metabolism in human.

It has been appreciated that nuclear receptors play important role in xenobiotic response by regulating expression and/or activity of drug-metabolizing enzymes, thereby modifying the targeted concentrations of the drug and altering the therapeutic drug response. With the development of molecular biology, structure biology, genetics and metabolism studies, tremendous effort has been made to understand the fundamental functions of nuclear receptor superfamily, which makes up a complex regulatory network with extensive cross communication in regulating the xenobiotic response between them.

GR becomes my focus not only because of the essential physiological process aforementioned but the key role it plays in drug metabolism. Exploring and understanding the fundamental mechanisms underpinning the actions of GR is critical and is of great help to explain the drug response and some pathophysilogical effects of glucocorticoids as well.

GR: structure

Glucocorticoid receptor belongs to subfamily 3C of nuclear receptor superfamily and is the first cloned human steroid receptor (Hollenberg et al., 1985). Two protein isoforms of GR, termed hGR alpha (777 amino acids) and hGR beta (742 amino acids) are distinguished by the last 15 amino acids at the C-terminal end and differed binding properties with glucocorticoids. hGR alpha is transcriptionally active while hGR beta is unable to bind glucocorticoids or induce gene transcription. Some studies suggest that it may act as a negative regulator of glucocorticoid action and contribute the tissue sensitivity to glucocorticoids (Bamberger et al., 1995).

Three major functional domains: N-terminal domain (NTD), DNA binding domain (DBD) and ligand-binding domain (LBD) are well studied for the GR. Within N-terminal domain, a major activational function domain1 (AF1) is required to enhance maximal transcriptional activity. The DBD contains the most conserved amino acid sequence and comprises two cysteine-rich zinc fingers, which are essential for GR dimerisation and site-specificity of DNA binding. The C-terminal located LBD is responsible for recognition and ligand binding.

It also contains the other activational function domain2 (AF2) and this AF2 is also important in regulating the transcriptional activity of GR.

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