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Target cells for cytochrome P450-catalysed irreversible binding of 7,12-dimethylbenz[a]anthracene (DMBA) in rodent adrenal
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology.
2002 In: Archives of Toxicology, Vol. 76, 460-466 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2002. Vol. 76, 460-466 p.
URN: urn:nbn:se:uu:diva-89546OAI: oai:DiVA.org:uu-89546DiVA: diva2:161119
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved
In thesis
1. Adrenal Bioactivation and Toxicity of 3-MeSO2-DDE, o,p´-DDD and DMBA Investigated in Tissue Slice Culture
Open this publication in new window or tab >>Adrenal Bioactivation and Toxicity of 3-MeSO2-DDE, o,p´-DDD and DMBA Investigated in Tissue Slice Culture
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

I developed a precision-cut adrenal slice culture procedure to investigate cytochrome P450 (CYP) catalysed irreversible binding and adrenocorticolytic effects in human, rodent, and fish adrenal tissue, ex vivo. Autoradiography and radioluminography of exposed tissue slices showed that the potent adrenal toxicant 3-methylsulphonyl-2,2´-bis(4-chlorophenyl)-1,1´-dichloroethene (MeSO2-DDE) causes a selective metabolite binding in zona fasciculata (ZF), which is diminished by the CYP11B1 inhibitor metyrapone. MeSO2-DDE also reduces corticosterone secretion, increases 11-deoxycorticosterone secretion and causes mitochondrial degeneration in ZF cells in cultured mouse adrenal slices. ACTH treatment of mice induces CYP11B1 and increases irreversible MeSO2-DDE binding and toxicity in ZF cells. Metyrapone-sensitive binding of MeSO2-DDE is also observed in human zona fasciculata/reticularis (ZF/ZR) and 11-deoxycorti- sol/corticosterone secretion increases in MeSO2-DDE-exposed cultured human adrenal slices. The adrenocorticolytic drug 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichlorethane (o,p´- DDD, Mitotane®) is also bound in ZF/ZR but does not to impair hormone secretion in human adrenal slices at equimolar concentration. A targeted, presumably CYP1B1-catalysed irreversible binding of the adrenocorticolytic carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) in ZF/ZR occurs in rat adrenal slices, whereas presumably CYP1A1-catalysed irreversible binding in endothelial cells is observed in CYP1-induced rats and mice. The rat-specific adrenocorticolytic activity of DMBA may rely on two independent pathological processes resulting in cell death and haemorrhage in the adrenal cortex. In Atlantic cod, selective binding of o,p´-DDD is observed in interrenal cells in cultured anterior kidney slices.

In conclusion, precision-cut adrenal slice culture is a simple ex vivo test system with which to investigate CYP-catalysed metabolite binding, alteredsteroid hormone secretion and target cell ultrastructure in human, experimental and wild animal tissue. The results imply that organisms under stress could be at increased risk of MeSO2-DDE induced adrenal toxicity. MeSO2-DDE is an expected human adrenal toxicant, which should be evaluated as a possible alternative in the therapy of adrenocortical hypersecretion and tumour growth.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 49 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 675
Developmental biology, adrenal cortex, 3-MeSO2-DDE, o, p´-DDD, DMBA, bioactivation, binding, toxic, Utvecklingsbiologi
National Category
Developmental Biology
Research subject
urn:nbn:se:uu:diva-1538 (URN)91-554-5185-3 (ISBN)
Public defence
2001-12-14, Lindahlsalen, Norbyv. 18A, Uppsala, 09:30
Available from: 2001-11-22 Created: 2001-11-22Bibliographically approved

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