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Toxicologically important DDT metabolites: Synthesis, enantioselective analysis and kinetics
Stockholm University, Faculty of Science, Department of Environmental Chemistry.
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 [en]
o, p'-DDD, 3-Methylsulfonyl-DDE, adrenocorticolytic compounds, chiral
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
URN: urn:nbn:se:su:diva-26952ISBN: 978-91-7155-829-9 (print)OAI: oai:DiVA.org:su-26952DiVA: diva2:212562
Public defence
2009-05-29, Magnélisalen, Svante Arrhenius väg 12 A, Stockholm, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-05-08 Created: 2009-04-21 Last updated: 2009-04-23Bibliographically approved
List of papers
1. Synthesis of 2-(4-chlorophenyl)-2-(4-chloro-3-thiophenol)-1,1-dichloroethene (3-SH-DDE) via Newman-Kwart rearrangement - A precursor for synthesis of radiolabeled and unlabeled alkylsulfonyl-DDEs
Open this publication in new window or tab >>Synthesis of 2-(4-chlorophenyl)-2-(4-chloro-3-thiophenol)-1,1-dichloroethene (3-SH-DDE) via Newman-Kwart rearrangement - A precursor for synthesis of radiolabeled and unlabeled alkylsulfonyl-DDEs
(English)Manuscript (Other academic)
Abstract [en]

For the first time, a pathway for synthesis of 2-(4-chlorophenyl)-2-(4-chloro-3-thiophenol)-1,1-dichloroethene (3-SH-DDE), is presented. The compound is of particular interest as a precursor for synthesis of alkylsulfonyl-DDE containing different alkyl groups to discover structural activity relationships, and to promote synthesis of radiolabeled methylsulfonyl-DDE. 2-Chloro-5-methylphenol was first methylated and further oxidized to the corresponding benzoic acid. The acid was reduced to the corresponding aldehyde (4-chloro-3-methoxy benzaldehyde) via 4-chloro-3-methoxy-benzene methanol. A lead/aluminium bimetal system was used to carry out the reductive addition of tetrachloromethane to 4-chloro-3-methoxy benzaldehyde to obtain 2,2,2-trichloro-1-(4-chloro-3-methoxyphenyl)ethanol, the desired starting material to synthesize the DDT-analogue (2-(4-chlorophenyl)-2-(4-chloro-3-methoxy-phenyl)-1,1,1-trichloroethane). Elimination of hydrochloric acid and removal of the methyl group led to the 3-OH-DDE. The Newman-Kwart rearrangement was applied to convert 3-OH-DDE to 3-SH-DDE via the dimethylcarbamothioate derivative. 3-SH-DDE is then used as a precursor for the radiolabel synthesis. The overall yield to acquire 3-SH-DDE after 11 steps was 3%. The step with the lowest yield was the DDT-analog synthesis with a yield of 30%. All other step had a yield of >50%. 3-SH-DDE was methylated with 14C-labeled iodomethane and oxidized by hydrogen peroxide to obtain 3-[14C]MeSO2-DDE in an overall yield of 30%.

Keyword
NKR, DDT, 14C
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26965 (URN)
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-01-14Bibliographically approved
2. Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p'-DDD (mitotane) in Minipigs.
Open this publication in new window or tab >>Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p'-DDD (mitotane) in Minipigs.
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2008 (English)In: Cancer Chemother Pharmacol, ISSN 0344-5704, Vol. 61, no 2, 267-274 p.Article in journal (Other academic) Published
Abstract [en]

The pharmacokinetics of the adrenocorticolytic drug candidate 3-Methylsulphonyl-DDE (3-MeSO(2)-DDE) and the anticancer drug o,p'-DDD (mitotane) were studied in Göttingen minipigs. The animals were given 3-MeSO(2)-DDE or o,p'-DDD as single oral doses (30 mg/kg). Concentrations in plasma and subcutaneous fat were measured by gas chromatography at different time points during 180 days. Maximal plasma concentrations appeared within 24 h for both compounds, but were about 2 times higher for 3-MeSO(2)-DDE. o,p'-DDD plasma concentrations declined rapidly to low levels during 4 days. 3-MeSO(2)-DDE also decreased rapidly, but remained at high concentrations throughout the study. In fat, 3-MeSO(2)-DDE reached about 25-fold higher levels than o,p'-DDD at 30 days, and both substances were eliminated slowly from this tissue. 3-MeSO(2)-DDE liver concentrations were about 18-fold higher than those in plasma at 180 days. In contrast, o,p'-DDD liver and plasma levels were about equal at 180 days. o,p'-DDD had roughly 45 times larger CL/F than 3-MeSO(2)-DDE, confirming that the elimination of this compound was more rapid. Both compounds were characterised by their localisation and retention in fat tissue, and the individual size of the fat stores clearly determined the plasma concentrations. It is concluded that although 3-MeSO(2)-DDE is an interesting candidate for therapeutic use due to its potential characteristics to specifically target adrenocortical tumour cells the slow elimination of the compound might make it challenging to design appropriate dosage regimes.

Identifiers
urn:nbn:se:su:diva-17536 (URN)000251009400009 ()17431626 (PubMedID)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2011-01-10Bibliographically approved
3. Toxicokinetics of the CYP11B1-activated adrenal toxicant 3-MeSO2-DDE in mother and offspring following oral administration to lactating minipigs
Open this publication in new window or tab >>Toxicokinetics of the CYP11B1-activated adrenal toxicant 3-MeSO2-DDE in mother and offspring following oral administration to lactating minipigs
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(English)Manuscript (Other academic)
Abstract [en]

3-Methylsulfonyl-4,4’-DDE (3-MeSO2-DDE) is a persistent and bioaccumulative metabolite of 4,4’-DDT, formed through biotransformation of 4,4’-DDE and characterized by a high and tissue-specific toxicity in the adrenal cortex in mouse fetuses, suckling pups and adult mice. 3-MeSO2-DDE also targets the human adrenal cortex kept in tissue-culture ex-vivo and human adrenocortical H295R cells in vitro. The present study was designed to examine the excretion of 3-MeSO2-DDE in milk and the maternal and neonatal toxicokinetics following a single oral dose to lactating minipigs. Milk, maternal fat, and plasma from five pigs and their suckling offspring were collected at regular intervals during four weeks. At autopsy on day 30 post partum, adrenals, liver and body fat were sampled from mothers and piglets. The levels of 3-MeSO2-DDE were measured by gas chromatography and the toxicokinetics in mothers and offspring were computed. The levels of 3-MeSO2-DDE in milk were considerably higher than in maternal and offspring plasma throughout the investigation. Based on both fresh weight and fat contents, the 3-MeSO2-DDE plasma levels in the piglets were about five times higher than in the mothers. A strong accumulation of 3-MeSO2-DDE was observed in fat tissue and a moderate accumulation in adrenals and liver of mothers and offspring. The retained tissue levels in the piglets were consistently higher than in the mothers. It is concluded that suckling offspring were more exposed than their mothers, which were given 3-MeSO2-DDE orally. The results suggest that human risk assessment of the adrenocorticolytic environmental pollutant 3-MeSO2-DDE should be focussed on breast-fed infants. Also in highly 4,4’-DDE- and 3-MeSO2-DDE-exposed marine mammals, the risks posed by 3-MeSO2-DDE are likely most pronounced during the postnatal period

Keyword
Göttingen minipig, toxicokinetics, milk, lactation, adrenal cortex
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26966 (URN)
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-01-14Bibliographically approved
4. Interindividual differences in o,p'-DDD enantiomer kinetics examined in Göttingen minipigs
Open this publication in new window or tab >>Interindividual differences in o,p'-DDD enantiomer kinetics examined in Göttingen minipigs
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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
Chiral analysis, enantioselective toxicokinetics, adrenocortical carcinoma, enantiomer fraction, absolute configuration
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26971 (URN)
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2010-01-14Bibliographically approved
5. Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
Open this publication in new window or tab >>Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
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]

1. Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. 2. 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. 3. 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. 4. 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. 5. 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.

Keyword
Adrenocortical cancer (ACC), mitotane, chirality, steroidogenesis
National Category
Environmental Sciences
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-26974 (URN)10.3109/00498250903470230 (DOI)000274882900002 ()
Note
authorCount :4Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2017-12-13Bibliographically approved
6. (2S)-1,1-dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethane
Open this publication in new window or tab >>(2S)-1,1-dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethane
2009 (English)In: Acta Crystallographica Section E: Structure Reports Online, ISSN 1600-5368, E-ISSN 1600-5368, Vol. 65(Pt 1), m9-m10 p.Article in journal (Other academic) Published
Abstract [en]

In the mol­ecule of the title compound, [HgCl2(C10H9N3)], the HgII atom is four-coordinated in a distorted tetra­hedral configuration by two N atoms from the chelating di-2-pyridylamine ligand and by two Cl atoms. In the crystal structure, inter­molecular N—HCl hydrogen bonds link the mol­ecules into centrosymmetric dimers. There is a π–π contact between the pyridine rings [centroid–centroid distance = 3.896 (5) Å].

National Category
Chemical Sciences
Research subject
Physical Chemistry
Identifiers
urn:nbn:se:su:diva-26975 (URN)10.1107/S1600536808040294 (DOI)
Available from: 2009-04-21 Created: 2009-04-21 Last updated: 2017-12-13Bibliographically approved

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