Synthesis of glucocorticoid-induced leucine zipper …
The different receptors, chiefly the GPCRs (G-Protein Coupled Receptors), Alpha and Beta-ADRs (Adrenergic Receptors), Growth Factor receptors, CRHR (Corticotropin Releasing Hormone Receptor), GcgR (Glucagon Receptor), DCC...
Cholesterol: Synthesis, Metabolism, Regulation
Phthalate esters (phthalates) such as dibutylphthalate (DBP) are commonly used as plasticisers and pesticides in a variety of products such as children‟s plastic toys, food packaging, cosmetics, medical equipment (including surgical equipment), and acaricides. Because of their widespread use phthalates are ubiquitous environmental contaminants that humans are commonly exposed to. Phthalates are known endocrine-disrupting chemicals (EDCs) that are well known to cause male reproductive defects such as cryptorchidism (failed descent of the testes) and hypospadias (malformations in the urethra) in a range of different species if they are exposed in utero. They do this by reducing testosterone production in Leydig cells, which are the primary site of testosterone biosynthesis in the male. Because phthalates are dose-additive they are considered to share the same mechanism of toxicity. However, the details of phthalates mechanism of toxicity are not fully understood. The aim of this research was to investigate the effects of DBP on the steroidogenesis pathway using the cultured rat Leydig cell cancer line R2C as a Leydig cell model. R2C cells were exposed to a range of DBP concentrations (10 μg/mL, 5 μg/mL, 1 μg/mL, and 0.1 μg/mL) and their steroid hormone production was analysed using reverse phase HPLC. R2C cells did not synthesise testosterone at detectable levels. However, DBP exposure stimulated cortisol biosynthesis at all concentrations but caused no change in progesterone biosynthesis. This cortisol stimulation in Leydig cells has not been observed before. Because cortisol and testosterone compete for precursors an increase in cortisol synthesis could starve testosterone synthesis of precursors. On top of this it has been shown that glucocorticoids including cortisol have an adverse effect on Leydig cell development reducing steroid production and even causing apoptosis. This could explain how DBP and other phthalates can cause male developmental defects such as cryptorchidism and hypospadias.
Figure 2. Regulation of steroid activity by 11β-hydroxysteroid dehydrogenase (11β-HSD). This enzyme exists in two isoforms that catalyze opposing conversions of cortisone to cortisol. The type 1 isozyme, which is expressed in the liver, converts inactive cortisone to cortisol. Cortisol can interact with both glucocorticoid (GR) and mineralocorticoid (MR) receptors. In contrast, the type 2 isoform converts active cortisol to inactive cortisone. This significantly reduces the effects of circulating cortisol on the mineralocorticoid receptors expressed in the collecting duct of the kidney, and minimizes the mineralocorticoid effect of normal levels of cortisol on the cells of the distal collecting duct. However, enzymatic inactivation can become saturated at extremely high levels of cortisol (such as in Cushing's disease), resulting in the development of sodium retention, fluid retention and hypertension. Type 2 HSD is also expressed by the placenta, which inactivates maternal cortisol before it reaches the fetus. A similar inactivation process also occurs for prednisolone. Hence both maternal cortisol, and prednisone/prednisolone given to the mother have little effect on fetal development. This is not true for some other synthetic glucocorticoids such as dexamethasone, that are not similarly affected by this enzyme.
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Glucocorticoid Receptor & Cotranscription Factors: ATF4, CEBPA, CEBPB, CREB1, CREB3, CREB3L4, NR3C1, POU2F1, POU2F2, STAT5A, STAT5B.
Steroid Hormone synthesis pathway (Clinical aspect)
Figure 1. Mechanism of action of glucocorticoids. The majority of effects produced by glucocorticoids result from initial steroid binding to intracellular glucocorticoid receptors followed by translocation to the nucleus and changes in gene transcription. In their steroid-free (unbound) state, intracellular glucocorticoid receptors (GR) are bound to stabilizing proteins that include heat-shock protein 90 (Hsp90) and immunophilin. The unbound form of the receptor is not capable of affecting gene transcription. Binding of steroid initiates a conformational change that results in an exchange of chaperone proteins, which permits attachment of the steroid-GR complex to the dynein protein trafficking pathway. This results in translocation of the steroid-GR complex from the cytoplasm into the nucleus (). Once in the nucleus, the steroid-GR complex dimerizes and binds to glucocorticoid response elements (GRE) associated with the regulatory region of glucocorticoid-sensitive genes. Binding of the glucocorticoid-GR dimer either represses, or stimulates the transcription of sensitive genes, resulting in changes in synthesis of mRNA, followed by changes in protein synthesis. These steps are necessary for producing most cellular responses to glucocorticoids, and . Both a , as well as are known to play important roles in mediating the antiinflammatory and immunomodulatory effects of glucocorticoids. As illustrated at the top left, in some situations glucocorticoids are able to produce more rapid responses by binding to membrane-associated receptors and exerting effects that do not involve changes in gene regulation. These non-genomic mechanisms remain poorly understood. COX: Cyclooxygenase; GR: Glucocorticoid receptor; Hsp: Heat Shock Protein(s); PLA2: Phospholipase A2.