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Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
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.
2010 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 3, 177-183 p.Article in journal (Refereed) Published
Abstract [en]

Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.

Place, publisher, year, edition, pages
2010. Vol. 40, no 3, 177-183 p.
National Category
Pharmaceutical Sciences Medical and Health Sciences
URN: urn:nbn:se:uu:diva-112582DOI: 10.3109/00498250903470230ISI: 000274882900002PubMedID: 20044879OAI: oai:DiVA.org:uu-112582DiVA: diva2:286782
Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2016-03-16
In thesis
1. In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE
Open this publication in new window or tab >>In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO2-DDE) is bioactivated by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of mice and forms irreversibly bound protein adducts, reduces glucocorticoid secretion, and induces cell death selectively in cortisol-producing adrenocortical cells. 3-MeSO2-DDE has therefore been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) therapy.

The aims of this thesis were to (1) develop in vitro test systems based on murine and human adrenocortical cell lines and to (2) investigate the mechanisms behind 3-MeSO2-DDE toxicity in adrenocortical cells.

The cytotoxic and endocrine-modulating effects of 3-MeSO2-DDE were compared to those of o,p′-DDD (mitotane), the current ACC therapy, and to those of several structurally analogous compounds in both murine and human cell lines. 3-MeSO2-DDE bioactivation and cytotoxicity proceeded in a similar manner in the murine adrenocortical Y-1 cell line as in mice in vivo. The effects were highly structure-specific. Moreover, 3-MeSO2-DDE formed irreversibly bound protein adducts and caused cell death also in the human H295R cell line, and was slightly more cytotoxic than o,p′-DDD. However, 3-MeSO2-DDE toxicity in human cells was not affected by the CYP11B1 inhibitor etomidate, suggesting that bioactivation in human cells is performed by additional/other enzyme(s) than CYP11B1. 3-MeSO2-DDE generated biphasic responses in cortisol and aldosterone secretion and in expression levels of the steroidogenic genes CYP11B1, CYP11B2, and StAR. Such hormesis-like responses were not seen for o,p′-DDD or the precursor DDT metabolite p,p′-DDE.

In addition, the two o,p′-DDD enantiomers (R)-(+)-o,p′-DDD and (S)-(-)-o,p′-DDD exhibited slight differences in cytotoxic and endocrine-modulating activity in H295R cells.

In conclusion, this thesis  provides  extended  knowledge  on  the  mechanisms  of  action  of 3-MeSO2-DDE and points out important differences in effects between murine and human cells. Lead optimisation studies of 3-MeSO2-DDE using the herein presented in vitro test systems are ongoing.


Place, publisher, year, edition, pages
Uppsala, Sweden: Acta Universitatis Upsaliensis, 2010. 57 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 744
Toxicity, 3-methylsulfonyl-DDE, CYP, adrenal cortex, metabolic activation, steroid hormones, Y-1, H295R, mitotane, adrenocortical carcinoma
National Category
Pharmacology and Toxicology
Research subject
Biology with specialization in Environmental Toxicology
urn:nbn:se:uu:diva-122721 (URN)978-91-554-7808-7 (ISBN)
Public defence
2010-06-01, Zootissalen, Evolutionsbiologiskt centrum (EBC), Villavägen 9, Uppsala, 09:00 (Swedish)
Available from: 2010-05-11 Created: 2010-04-16 Last updated: 2010-05-18Bibliographically approved

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