uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
2002 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 16, no 2, 113-121 p.Article 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.

Place, publisher, year, edition, pages
2002. Vol. 16, no 2, 113-121 p.
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89829DOI: 10.1016/S0887-2333(01)00111-4PubMedID: 11869873OAI: oai:DiVA.org:uu-89829DiVA: diva2:161631
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2013-06-10Bibliographically approved
In thesis
1. Interaction of Xenobiotics with the Glucocorticoid Hormone System in vitro
Open this publication in new window or tab >>Interaction of Xenobiotics with the Glucocorticoid Hormone System in vitro
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. 48 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 716
Keyword
Biology, DDT, PCB, tolylfluanid, adrenal, CYP11B1, glucocorticoid receptor, endocrine disrupter, Biologi
National Category
Biological Sciences
Research subject
Ecotoxicology
Identifiers
urn:nbn:se:uu:diva-2012 (URN)91-554-5321-X (ISBN)
Public defence
2002-05-24, Lindahlsalen, Uppsala, 09:15
Opponent
Available from: 2002-05-02 Created: 2002-05-02Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
By organisation
Environmental Toxicology
In the same journal
Toxicology in Vitro
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 650 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf