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Interaction of Xenobiotics with the Glucocorticoid Hormone System in vitro
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Environmental Toxicology.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Persistent environmental pollutants were examined for their interaction with the glucocorticoid hormone system. The focus was placed on interference with the glucocorticoid synthesis and the glucocorticoid-signalling pathway in various in vitro test systems.

Several aryl methyl sulphones competitively inhibited CYP11B1 activity in mouse adrenocortical Y1 cells. The DDT metabolite, 3-methylsulphonyl-2,2’-bis(4-chlorophenyl)-1,1’-dichloroethene (3-MeSO2-DDE) had a higher affinity to the enzyme than the endogenous substrate, 11-deoxycorticosterone. In fact, 3-MeSO2-DDE (Ki 1.6 μM) was almost as potent as the drug metyrapone (Ki 0.8 μM), a well-known inhibitor of the enzyme. 3-MeSO2-DDE inhibited CYP11B1 activity in human adrenocortical H295R carcinoma cells, and at higher concentrations the CYP21 activity. The human H295R cell line seems to be a useful test system for studies of enzyme activities and could be used to screen endocrine disrupting chemicals interfering with the glucocorticoid hormone synthesis.

Several chiral PCB methyl sulphones and the fungicide tolylfluanid proved to be antagonists to the glucocorticoid receptor (GR) in rat hepatoma cells and/or Chinese hamster ovary cells stable transformed with a human GR and a responsive reporter vector. The 4-methylsulphonyl-2,3,6,2’,4’,5’-hexachlorobiphenyl (4-MeSO2-CB149) enantiomers had similar antagonistic effect on the GR. Co-exposure of substances led to additive inhibitory effects on glucocorticoid-regulated protein synthesis in rat hepatoma cells. In general, 4-substituted but not 3-substituted methylsulphonyl-PCBs interacted with the glucocorticoid hormone system.

In the environment, humans and wildlife are constantly exposed to a wide range of chemicals. Considering the effects of these substances via mechanisms of actions described in this thesis, interference of xenobiotics with the glucocorticoid hormone system deserves further attention. In conclusion, environmental pollutants can interact with the glucocorticoid hormone system in vitro, yet the effects of the tested substances on this hormone system remain to be established in vivo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 48
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 716
Keyword [en]
Biology, DDT, PCB, tolylfluanid, adrenal, CYP11B1, glucocorticoid receptor, endocrine disrupter
Keyword [sv]
Biologi
National Category
Biological Sciences
Research subject
Ecotoxicology
Identifiers
URN: urn:nbn:se:uu:diva-2012ISBN: 91-554-5321-X (print)OAI: oai:DiVA.org:uu-2012DiVA, id: diva2:161635
Public defence
2002-05-24, Lindahlsalen, Uppsala, 09:15
Opponent
Available from: 2002-05-02 Created: 2002-05-02Bibliographically approved
List of papers
1. Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones
Open this publication in new window or tab >>Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones
1998 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 83, no 5, p. 225-230Article in journal (Refereed) Published
Abstract [en]

The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-89828 (URN)10.1111/j.1600-0773.1998.tb01473.x (DOI)9834972 (PubMedID)
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2017-12-14Bibliographically approved
2. Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line
Open this publication in new window or tab >>Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line
2002 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 16, no 2, p. 113-121Article in journal (Refereed) Published
Abstract [en]

The formation of steroids in the H295R human adrenocortical carcinoma cell line was analysed by HPLC or RIA, and based on these data the apparent catalytic activities of CYP11A, CYP17, CYP21 and CYP11B1 in this cell line were calculated. The environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) and the cytochrome P450 (CYP) inhibitors ketoconazole, metyrapone and aminoglutethimide were studied for their effects on the steroid formation. Metyrapone (IC50) of 1 microM) and 3-MeSO2-DDE (10 microM: 66 +/- 10% of control) were found to inhibit the apparent CYP11B1 activity. Ketoconazole inhibited all enzymes examined with the greatest effects on CYP11B1 (IC50) of 2.5 microM). Aminoglutethimide was examined only for effects on CYP11A activity and was shown to inhibit pregnenolone formation (20 microM: 61 +/- 4% of control). The possibility of studying all CYP enzymes in the corticosteroidogenesis makes this cell line a valuable test system to examine effects of chemicals, such as suspected endocrine disruptors, on the human glucocorticoid hormone synthesis. The inhibition of cortisol formation by 3-MeSO2-DDE supports an interaction with the active site of CYP11B1, as previously reported in mouse adrenocortical Y1 cells. In mice, this interaction led to metabolic activation and a high adrenotoxicity of 3-MeSO2-DDE. Therefore studies on the adrenotoxicity of 3-MeSO2-DDE in humans are needed.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-89829 (URN)10.1016/S0887-2333(01)00111-4 (DOI)11869873 (PubMedID)
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2017-12-14Bibliographically approved
3. Interactions between methylsulfonyl PCBs and the glucocorticoid receptor
Open this publication in new window or tab >>Interactions between methylsulfonyl PCBs and the glucocorticoid receptor
1998 (English)In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 106, no 12, p. 769-772Article in journal (Refereed) Published
Abstract [en]

Persistent polychlorinated biphenyl (PCB) metabolites were studied with respect to their interaction with the human glucocorticoid receptor (GR). 3-Methylsulphonyl-2,5,6,2',4',5'-hexachlorobiphenyl (3-MeSO2-CB149) was shown to compete with 3H-dexamethasone for binding to the GR, with an IC50 (concentration that inhibits 50%) of approximately 1 microM. Using GRAF cells expressing human GR, glucocorticoid responsive element, and a reporter enzyme, we demonstrated that 3-MeSO2-CB149 functionally acts as an antagonist at the GR (IC50 = 2.7 microM). In accordance with the receptor binding, the antagonism mainly appeared to be of a competitive nature. When studying the competitive binding of 24 methylsulfonyl PCBs (relative to dexamethasone) to GR from mouse liver cytosol, seven compounds had a higher affinity to GR than 3-MeSO2-CB149. Structure-activity relationship studies indicated that the presence of three chlorine atoms in the ortho-position and chlorine and methyl sulfone groups on either end of the molecule (4 and 4'-position) increased the affinity to GR. The relevance of this finding for human health is not known, but PCB methyl sulfones are ubiquitous pollutants present in mother's milk. The results stress the need for studying endocrine disruptors that affect hormonal systems other than sex and thyroidogenic hormones.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-89830 (URN)9831536 (PubMedID)
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2017-12-14Bibliographically approved
4. Xenobiotics and the glucocorticoid receptor: Additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells
Open this publication in new window or tab >>Xenobiotics and the glucocorticoid receptor: Additive antagonistic effects on tyrosine aminotransferase activity in rat hepatoma cells
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89831 (URN)
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2010-01-13Bibliographically approved
5. Enantiomeric methylsulfonyl-2,2',4',5,5',6-PCB; differences in biliary excretion but similar effects on the glucocorticoid-signalling pathway
Open this publication in new window or tab >>Enantiomeric methylsulfonyl-2,2',4',5,5',6-PCB; differences in biliary excretion but similar effects on the glucocorticoid-signalling pathway
Show others...
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89832 (URN)
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2010-01-13Bibliographically approved

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