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Species differences in 3-methylsulphonyl-DDE bioactivation by adrenocortical tissue
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
2008 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 82, no 3, 159-163 p.Article in journal (Refereed) Published
Abstract [en]

The CYP11B1-activated adrenocortical toxicant 3-methylsulphonyl-DDE (3-MeSO2-DDE) is proposed as a lead compound for an improved chemotherapy for adrenocortical carcinoma. We compared the binding of 3-MeSO2-[C-14]DDE in the adrenal cortex of four rodent species; hamster, guinea pig, mouse and rat, using a precision-cut adrenal slice culture system ex vivo. Localization and quantification of the bound radioactivity were carried out using light microscopy autoradiography and radioluminography. The results revealed major species differences since 3-MeSO2-[C-14]DDE was extensively bound to the hamster adrenal tissue while the guinea pig adrenals were devoid of binding. A high binding in mouse adrenal cortex was confirmed while binding in rat adrenal cortex was very weak. The results support previous observations that metabolic activation of 3-MeSO2-DDE is highly species dependent. Since CYP11B1 could be expressed in tissues other than the adrenal cortex, final toxicological characterization should be carried out in a species that can bioactivate this compound.

Place, publisher, year, edition, pages
2008. Vol. 82, no 3, 159-163 p.
Keyword [en]
3-MeSO2-DDE, hamster, guinea pig, CYP450, irreversible binding, adrenal, tissue-slice
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-96126DOI: 10.1007/s00204-007-0264-8ISI: 000254241200003PubMedID: 18034334OAI: oai:DiVA.org:uu-96126DiVA: diva2:170598
Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Adrenocorticolysis Induced by 3-MeSO2-DDE: Mechanisms of Action, Kinetics and Species Differences
Open this publication in new window or tab >>Adrenocorticolysis Induced by 3-MeSO2-DDE: Mechanisms of Action, Kinetics and Species Differences
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The DDT metabolite 3-methylsulphonyl-DDE (3-MeSO2-DDE) induces cell death specifically in the adrenal cortex of mice after a cytochrome P45011B1 (CYP11B1)-catalysed bioactivation. This substance is not only an environmental pollutant, but also a suggested lead compound for an improved chemotherapy of adrenocortical carcinoma (ACC). The aim of the thesis was to further investigate this compound in terms of kinetics, cell death mechanisms and species differences. The pharmacokinetics of 3-MeSO2-DDE and the current drug for ACC, o,p’-DDD, was studied during 6 months following a single dose in minipigs. The elimination was slower for 3-MeSO2-DDE than for o,p’-DDD, indicated by a lower clearance and longer t½ in plasma and subcutaneous fat. Both substances remained in fat tissue during the whole study period. Unlike o,p’-DDD, 3-MeSO2-DDE was retained also in liver. The adequacy of the murine adrenocortical cell line Y-1 was evaluated for studies of adrenotoxic compounds. The Y-1 cells proved to be an appropriate test system for future mechanism studies, since CYP-catalysed irreversible binding, inhibited corticosterone production induced by 3-MeSO2-DDE and o,p’-DDD were successfully demonstrated. Cell death of 3-MeSO2-DDE in the mouse adrenal cortex was implied to be necrotic. Early apoptotic signalling (i.e. up-regulation of caspase-9) was observed, although it seemed to be interrupted by ATP-depletion and anti-apoptotic actions by heat shock protein 70, resulting in lack of activation of caspase-3. Using cultured adrenal tissue slices, two not previously studied species were examined ex vivo regarding adrenal binding of 3-MeSO2-[14C]DDE. Binding was found in the hamster adrenal cortex and in assumed cortical cells in the medulla, while the guinea pig adrenal was devoid of binding. This emphasises the species specificity in bioactivation of 3-MeSO2-DDE. The thesis forms a basis for further investigations in the human adrenocortical cell line H295R and provides new knowledge of importance for toxicological risk assessment of 3-MeSO2-DDE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 331
Keyword
Toxicology, 3-methylsulphonyl-DDE, o, p'-DDD, CYP11B1, adrenal cortex, tissue-specific toxicity, bioactivation, kinetics, Y-1 cells, Toxikologi
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-8180 (URN)978-91-554-6950-4 (ISBN)
Public defence
2007-09-29, Lindahlsalen, Evolutionsbiologiskt centrum (EBC), Norbyvägen 18 A, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2007-09-06 Created: 2007-09-06 Last updated: 2011-01-20Bibliographically approved

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