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Disruption of Glucocorticoid and Mineralocorticoid Receptor-Mediated Responses by Environmental Chemicals

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Disruption of Glucocorticoid and Mineralocorticoid Receptor-Mediated Responses by Environmental Chemicals ENDOCRINE DISRUPTORS: BASIC RESEARCH AND METHODS 335 doi:10.2533/chimia.2008.335 CHIMIA 2008, 62, No. 5 Chimia 62 (2008) 335–339 © Schweizerische Chemische Gesellschaft ISSN 0009–4293 Disruption of Glucocorticoid and Mineralocorticoid Receptor-Mediated Responses by Environmental Chemicals Alex Odermatt* and Christel Gumy Abstract: Glucocorticoids and mineralocorticoids are key endocrine hormones modulating essential physiological processes such as energy metabolism, cell growth and differentiation, maintenance of blood pressure and immune responses. Despite their importance and the fact that their impaired function has been associated with various diseases, there are only few studies on the potential disruption of glucocorticoid and mineralocorticoid action by xenobiotics. To facilitate the identification and characterization of such chemicals, we established cell-based as- says to determine the impact of xenobiotics on different steps of corticosteroid hormone action. Screening of a small library of chemicals led to the identification of several compounds inhibiting the 11β -hydroxysteroid dehy- drogenase (11β -HSD) prereceptor enzymes 11β -HSD1 and/or 11β -HSD2 and of chemicals blocking the function of glucocorticoid receptors (GR) and mineralocorticoid receptors (MR). These findings build a basis to extend the search for chemicals acting on additional targets of the corticosteroid hormone pathway and to apply in silico prediction tools in combination with biological testing to screen large numbers of chemicals. The identification of chemicals interfering with corticosteroid action and the elucidation of the underlying molecular mechanisms are relevant with respect to the potential contribution to common diseases such as metabolic syndrome, immune diseases, brain disorders and cancer. Keywords: Cortisol · Endocrine disruptor · Glucocorticoid receptor · Glucocorticoid · 11β -Hydroxysteroid dehydrogenase · Mineralocorticoid receptor · Xenobiotics 1. Physiological Role cell cycle control, and modulation of stress are produced in the adrenal cortex involv- of Glucocorticoids and and inflammatory responses (Fig. 1).[1] An ing several steroidogenic enzymes, and Mineralocorticoids impaired regulation of glucocorticoid ac- the synthesis of these hormones is tightly tion has been associated with various com- regulated by corticotrophin releasing fac- Corticosteroid hormones are divided into plications including metabolic and cardio- tor (CRF) and adrenocorticotrophic hor- glucocorticoids (cortisol in humans and vascular diseases, osteoporosis, cataracts, mone (ACTH) via the hypothalamus-pitu- corticosterone in rodents) and mineralocor- immune diseases, mood and cognitive dis- itary-adrenal (HPA) axis. Glucocorticoids ticoids (aldosterone). They are involved in orders and cancer. [2− 5] Disturbances of min- control their own synthesis by a negative the regulation of many physiological pro- eralocorticoid action have been linked to feedback response mediated by inhibition cesses, including energy metabolism, elec- the occurrence of hypertension and cardio- of CRF and ACTH. Upon release into the trolyte and blood pressure control, bone vascular diseases.[6,7] The incidence of these blood stream, corticosteroid hormones are metabolism, regulation of brain function, complex diseases increases with increasing mainly bound to carrier proteins (transcor- age, and in addition to genetic predispo- tin, albumin) and reach cells in peripheral sition, factors including life style and the tissues. exposure to xenobiotics are likely to play At the cellular level, cortisol or corti- a role in these pathological processes. In de- costerone exert their action through GR and veloped countries, the exposure to chemi- aldosterone acts by activating MR. Impor- cals from the environment may contribute tantly, the local activation of the receptors is to the high incidence of allergic diseases, controlled by two distinct 11β -HSD prere- cancer and metabolic disturbances.[8− 10] ceptor enzymes.[11] 11β -HSD1 is expressed ubiquitously and catalyzes predominantly * Correspondence: Dr. A. Odermatt the reduction of inactive 11-ketoglucocor- Molecular and Systems Toxicology 2. Major Targets of the ticoids (cortisone, 11-dehydrocortisone) Department of Pharmaceutical Sciences University of Basel Corticosteroid Hormone Pathway into active 11β -hydroxyglucocorticoids Klingelbergstrasse 50 (cortisol, corticosterone).[12] This enzyme CH-4056 Basel Exogenous chemicals can cause distur- has a crucial role in potentiating local GR Tel.: +41 61 267 1530 Fax: +41 61 267 1515 bances of corticosteroid hormone action activation in metabolic processes and in the E-mail: [email protected] at several steps (Fig. 2). Corticosteroids immune system. ENDOCRINE DISRUPTORS: BASIC RESEARCH AND METHODS 336 CHIMIA 2008, 62, No. 5 fact that they belong to different classes of proteins and share very low sequence simi- larity. This suggests that the binding pockets of these proteins share structural similarity and that the chemicals mimicking corticos- teroid molecules might interact with more than one of these proteins. Thus, to assess the potential disruption of corticosteroid hormone action by exogenous chemicals, suitable bioassays are required to measure the activities of the different proteins, with roles in regulation, biosynthesis, transport, intracellular metabolism, receptor and deg- radation. 3. Bioassays Compared to the extensively studied field of estrogen- and androgen-like ac- tions by environmentally relevant chemi- cals, there are only few studies focusing on corticosteroid hormones.[16] As a start- ing point to identify chemicals that act on Fig. 1. Overview of physiological functions that are regulated by corticosteroid hormones different steps of glucocorticoid and min- eralocorticoid regulation, we established assays to measure the function of human corticosteroid hormone receptors (GR and MR) and glucocorticoid metabolizing en- zymes (11β -HSD1 and 11β -HSD2). To distinguish between different steps of re- ceptor activation, the HEK-293 cell line was selected that is devoid of endogenous expression of corticosteroid receptors and hormone metabolizing enzymes.[17] Other cells that are suitable alternatives include COS-1 and CV-1 cells,[18] but they are not of human origin. Receptor activity was measured in intact cells transiently expressing recombinant receptor or a green-fluorescence (GFP)- chimeric receptor. This allowed the assess- ment of the effect of a given chemical on ligand binding to the receptor, subsequent translocation of the receptor into the nucle- us and receptor-mediated transcriptional activation of a reporter gene. It is important to distinguish the different steps of recep- tor activation to understand the inhibitory Fig. 2. Schematic overview of targets of corticosteroid hormone action mechanism of a chemical. Spironolactone, as an example, efficiently binds to MR and induces translocation of the receptor into the nucleus. It acts as a partial agonist and The second enzyme, 11β -HSD2, is tects the fetus from high maternal gluco- therefore antagonizes the potent agonist expressed in cortical collecting ducts corticoid concentrations.[15] effect of aldosterone. The bile acid cheno- and distal tubules in the kidney and The tissue-dependent responses upon deoxycholic acid inhibits 11β -HSD2 and in distal colon, where it protects MR activation of GR and MR strongly depend leads to glucocorticoid-induced activation from glucocorticoids by converting on the presence of coactivator and corepres- of MR. Although it also induces nuclear 11β -hydroxyglucocorticoids into 11-keto- sor proteins that interact with the receptor translocation of MR in the absence of glucocorticoids.[13] The MR has similar complex, as well as on post-translational 11β -HSD2, chenodeoxycholic acid neither affinities to bind aldosterone and cortisol modifications of both receptor and associ- activates nor antagonizes MR activation by and circulating concentrations of the latter ated proteins. Finally, enzymes responsible cortisol or aldosterone.[19,20] are 100− 1000 times higher, thus, the close for the degradation and excretion of the ste- To assess the effect of chemicals on proximity of 11β -HSD2 to the receptor al- roid hormones are important to terminate 11β -HSD prereceptor enzyme function, lows aldosterone to bind.[14] 11β -HSD2 is hormone action. the conversion of cortisone to cortisol or the also expressed in the syncytiotrophoblast The proteins described above all recog- reverse reaction was measured in lysates or layer of the human placenta, where it pro- nize corticosteroid molecules despite the intact HEK-293 cells stably expressing C- ENDOCRINE DISRUPTORS: BASIC RESEARCH AND METHODS 337 CHIMIA 2008, 62, No. 5 terminally FLAG-tagged human 11β -HSD1 identified, compounds are responsible for with 11β -HSD2 function by modification or 11β -HSD2.[21] The impact of 11β -HSD inhibition of 11β -HSD2. Additional com- of cysteine residues. Dithiothreitol, but enzyme inhibition on receptor function pounds of the triterpenoid and flavonoid not glutathione, protected from organotin- was determined in cells cotransfected with class of chemicals that inhibited 11β -HSD2 dependent inhibition. Enhanced glucocor- 11β -HSD1 and GR or 11β -HSD2 and MR, include abietic acid, gossypol, magnolol ticoid concentrations, due to disruption of respectively. As controls for 11β -HSD1 and and tea polyphenols. However, their rela- 11β -HSD2 function, may contribute to the 11β -HSD2 the well
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