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

Direct link
Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
1998 (English)In: Pharmacology and Toxicology, ISSN 0901-9928, Vol. 83, no 5, 225-230 p.Article 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.

Place, publisher, year, edition, pages
1998. Vol. 83, no 5, 225-230 p.
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-89828DOI: 10.1111/j.1600-0773.1998.tb01473.xPubMedID: 9834972OAI: oai:DiVA.org:uu-89828DiVA: diva2:161630
Available from: 2002-05-02 Created: 2002-05-02 Last updated: 2013-05-30Bibliographically 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.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 716
Biology, DDT, PCB, tolylfluanid, adrenal, CYP11B1, glucocorticoid receptor, endocrine disrupter, Biologi
National Category
Biological Sciences
Research subject
urn:nbn:se:uu:diva-2012 (URN)91-554-5321-X (ISBN)
Public defence
2002-05-24, Lindahlsalen, Uppsala, 09:15
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
Pharmacology and Toxicology
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 261 hits
ReferencesLink to record
Permanent link

Direct link