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Title: Investigation of the cellular and physiological effects of 5 alpha-tetrahydro reduced glucocorticoids in vitro and in vivo
Author: Yang, Chenjing
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2010
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Glucocorticoids have been the most widely used anti-inflammatory drugs. However, chronic excessive exposure to glucocorticoids causes numerous side effects, including obesity, hypertension and type II diabetes. Thus dissociated steroids with anti-inflammatory efficacy and reduced metabolic side effects are an attractive therapeutic goal. A previous study has shown that 5a-tetrahydro corticosterone (5aTHB), produced by steroid 5a-reductases in rodents, is an activator of glucocorticoid receptor (GR). Therefore, we hypothesized that 5aTHB may possess some of the properties of the parent steroid to transactivate and transrepress genes regulated by GR and have shown it possesses some of the characteristics of a dissociated steroid. In cultured cells, 5aTHB has weaker effects than corticosterone to induce GR translocation but was synergistic with corticosterone. 5cxTHB did not induce the expression of PEPCK or TAT or glucocorticoid responsive reporter genes. In contrast however in bone marrow derived macrophages, 5aTHB increased the secretion of anti-inflammatory cytokine IL-10 and suppressed LPS-induced production of pro-inflammatory cytokines TNFa and IL-6. In C57BL/6 mice following acute administration of 5aTHB, glucose tolerance and insulin sensitivity were not affected, and hepatic PEPCK and TAT were not increased. In mice that were chronically infused with 5aTHB, body and organ weights, glucose tolerance, insulin sensitivity, or expression of glucocorticoid responsive genes in liver and adipose tissue were not changed. Elowever circulating ACTH was suppressed and in whole blood, LPS-induced production of TNFa was suppressed. In mice suffering from peritonitis induced by LPS, 5aTHB suppressed IL-6 levels in peritoneal fluid to a similar extent as corticosterone. Therefore the contribution of 5a-reductase type 1 (5aRl) to protect metabolic tissues from adverse metabolic effects of glucocorticoids was tested in 5aRl deficient mice. Circulating corticosterone was elevated in animals receiving corticosteroid with no difference between genotypes. Infusion of corticosterone induced a greater elevation in insulin and free fatty acids during a glucose tolerance test in 5aRl-null mice, compared to wild-type controls. In the mesenteric adipose tissue, angiotensinogen expression was only increased in 5aRl-null mice receiving corticosterone. However suppression of TNFa and IL-6 by corticosterone in the whole blood was independent of genotype. In conclusion, 5aTHB is a weak GR ligand, but possesses some anti-inflammatory properties similar to those of corticosterone, potentially acting through GR-protein interactions as opposed to GR-GRE interactions. 5aTHB could be a prototype for a selective anti-inflammatory drug with limited metabolic toxicity. Thus inhibition of 5aRl may cause detrimental metabolic effects without inducing immune suppression.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available