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Interindividual differences in o,p'-DDD enantiomer kinetics examined in Göttingen minipigs
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
Department of Environmental Toxicology, Uppsala University.
Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry. (Division of Structural Chemistry)
Department of Environmental Toxicology, Uppsala University.
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(English)Manuscript (Other (popular science, discussion, etc.))
Abstract [en]

Five minipigs were given a single oral dose of a racemic mixture of o,p’-DDD (30 mg kg-1 b.w., EF = 0.49). Blood plasma and subcutaneous adipose tissue were collected for analysis, at different time-points over 180 d. At the end of the experiment also liver, kidney and brain tissue were collected. Low concentrations of o,p’-DDD still remained after 180 d in plasma (mean 0.5 ±0.3 ng g-1 f.w.) and in adipose tissue (mean 40 ±40 ng g-1 f..w.). The mean concentrations in liver and kidney were 500 ±300 pg g-1 f.w. and 90 ±50 pg g-1 f.w. respectively. The enantiomers of o,p’-DDD were isolated by HPLC and the absolute configuration of the enantiomers were determined by X-ray crystallography and polarimetry as R-(+)-o,p’-DDD and S-(-)-o,p’-DDD. The enantiomer fractions (EFs) of o,p’-DDD were determined in plasma, adipose tissue and kidney using GC/ECD equipped with a chiral column. The EFs of o,p’-DDD in the individual minipigs showed large variability, ranging from 0.2-0.6 after 24 h in plasma and from 0.2-0.7 after 90 d in adipose tissue. Hence in two of the minipigs, the S-(-)-o,p’-DDD enantiomer was dominating while the other enantiomer, R-(+)-o,p’-DDD was dominating in three minipigs. We propose that a yet not identified factor related to polymorphism, regulating the metabolism and/or elimination of the enantiomeric o,p´-DDD, is responsible for the differences in enantiomeric retention of the compound in the minipigs.

Keyword [en]
Chiral analysis, enantioselective toxicokinetics, adrenocortical carcinoma, enantiomer fraction, absolute configuration
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
URN: urn:nbn:se:su:diva-26971OAI: oai:DiVA.org:su-26971DiVA: diva2:212146
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
Open this publication in new window or tab >>Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

DDT was extensively and globally used as a pesticide in agriculture and for malaria vector control from the 1940’s until the 1970’s. Due to its heavy use, DDT became ubiquitously distributed throughout the environment. DDT and several DDT metabolites are persistent organic pollutants. Two DDT metabolites, 3-MeSO2-DDE and o,p’-DDD have been proved to be tissue specific toxicants in the adrenal cortex. They are bioactivated to reactive intermediates which bind covalently to the adrenal cortex causing cell death. Due to its tissue specific toxicity o,p’-DDD has been used as a chemotherapy drug for adrenal cancer in humans. The efficacy and potency is however low and o,p’-DDD treatment is associated with serious side effects. 3-MeSO2-DDE has been suggested as a potential alternative therapeutic agent.

A key aim of this thesis has been to improve the understanding of the kinetics of the two adrenocorticolytic compounds o,p’-DDD, its two enantiomers and 3-MeSO2-DDE. To meet this objective chemical synthesis and enantioselective analysis were required. Furthermore, in vitro toxicity of o,p’-DDD enantiomers and diastereomers were performed.

An 11 step synthesis of 3-SH-DDE has been developed to promote both labelled and unlabelled synthesis of 3-alkylsulfonyl-DDE. Toxicokinetic studies showed that 3-MeSO2-DDE and o,p’-DDD were accumulated in tissues and retained in adipose tissue in minipigs. 3-MeSO2-DDE however had a twice as long biological t1/2 and a considerably lower Vd compared to o,p’-DDD. Suckling offspring were more exposed to 3-MeSO2-DDE than their mothers who were given 3-MeSO2-DDE orally. Interindividual differences in enantiomer kinetics in minipigs were observed suggesting polymorphism among the minipigs. Preparative isolation of the o,p’-DDD enantiomers is presented allowing determination of the absolute structures of the o,p’-DDD enantiomers by X-ray. The pure enantiomer of o,p’-DDD showed significant differences in toxicity in human adrenocortical cells.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Chemistry, Stockholm Univerisity , 2009. 55 p.
Keyword
o, p'-DDD, 3-Methylsulfonyl-DDE, adrenocorticolytic compounds, chiral
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26952 (URN)978-91-7155-829-9 (ISBN)
Public defence
2009-05-29, Magnélisalen, Svante Arrhenius väg 12 A, Stockholm, 10:00 (Swedish)
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Supervisors
Available from: 2009-05-08 Created: 2009-04-21 Last updated: 2009-04-23Bibliographically approved

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