| 1. |
- Asp, Vendela, et al.
(författare)
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Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
- 2010
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Ingår i: Xenobiotica. - : Informa UK Limited. - 0049-8254 .- 1366-5928. ; 40:3, s. 177-183
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Cantillana, T, et al.
(författare)
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(2S)-1,1-dichloro-2-(2-chlorophenyl)-2-(4-chlorophenyl)ethane
- 2009
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Ingår i: Acta Crystallographica Section E. - 1600-5368. ; 65(Pt 1), s. m9-m10
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- 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].
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| 3. |
- cantillana, T., et al.
(författare)
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Interindividual differences in o,p'-DDD enantiomer kinetics examined in Göttingen minipigs
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Annan publikation (populärvet., debatt m.m.)abstract
- 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.
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| 4. |
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| 5. |
- Cantillana, T., et al.
(författare)
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Interindividual differences in o,p'-DDD enantiomer kinetics examined in Göttingen minipigs
- 2009
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 76:2, s. 167-172
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Tidskriftsartikel (refereegranskat)abstract
- 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 to 0.6 after 24h in plasma and from 0.2 to 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.
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| 6. |
- Cantillana, T., 1969-, et al.
(författare)
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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
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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%.
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| 7. |
- Cantillana, T., 1969-, et al.
(författare)
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Toxicokinetics of the CYP11B1-activated adrenal toxicant 3-MeSO2-DDE in mother and offspring following oral administration to lactating minipigs
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- 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
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| 8. |
- Fred, Charlotta, et al.
(författare)
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Adducts to N-terminal valines in hemoglobin from isoprene di-epoxide, a metabolite of isoprene
- 2004
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Ingår i: Rapid Communications in Mass Spectrometry. - : John Wiley & Sons, Inc. - 0951-4198 .- 1097-0231. ; 18:18, s. 2177-2184
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Tidskriftsartikel (refereegranskat)abstract
- Isoprene (2-methylbuta-1,3-diene) is a multi-site carcinogen in rodents. To evaluate the role of the diepoxide metabolite (1,2:3,4-diepoxy-2-methylbutane) in carcinogenesis, measurements of in vivo doses of the diepoxide are needed. The in vivo dose may be inferred from levels of reaction products with hemoglobin (Hb adducts). This report presents in vitro studies of the adduct formation by the diepoxide of isoprene with valinamide and oligopeptides as model compounds of N-terminal valines in hemoglobin (Hb). In the reaction with valinamide it was shown that isoprene diepoxide forms as the main product a ring-closed adduct, which is a pyrrolidine derivative [N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valinamide, MPyr-Val]. The analysis was performed by gas chromatography/mass spectrometry (GC/MS) (EI and PICI) after acetylation. The ring-closed adduct was also identified by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) as the main product in the reaction between isoprene diepoxide and standard hepta- or (2H8)octapeptides, corresponding to the N-terminal peptides of the α-chains in mouse and rat Hb. These peptides, alkylated with isoprene diepoxide, to be used as internal standards and calibration standards for quantification of MPyr-adduct levels in vitro and in vivo, were analyzed with respect to the degree of MPyr-alkylation by two independent methods, amino acid analysis and HPLC-UV; similar results were obtained using these methods. A method for measurement of Hb adducts as modified peptides, used earlier to measure a similar adduct to N-terminal valines in Hb from the diepoxide of 1,3-butadiene, has in the present work been tested for application to isoprene diepoxide. The method is based on tryptic degradation of globin and LC/ESI-MS analysis of N-terminal Pyr-heptapeptides of the Hb α-chain enriched by HPLC. MPyr-adduct levels in isoprene diepoxide alkylated hemolysate from mouse erythrocytes incubated with different concentrations of isoprene diepoxide (2 and 10 mM) for 1 h were quantified. The adduct level was about 50 nmol/g α-chain Hb per mM × h. From the adduct levels the rate constant of isoprene diepoxide for reaction with N-terminal valine was calculated to be about 1.6 times faster than for diepoxybutane
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