uu.seUppsala universitets publikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Pharmacokinetics of the adrenocorticolytic compounds 3-methylsulphonyl-DDE and o,p′-DDD (mitotane) in Minipigs
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
Visa övriga samt affilieringar
2008 (Engelska)Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 61, nr 2, s. 267-274Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The pharmacokinetics of the adrenocorticolytic drug candidate 3-Methylsulphonyl-DDE (3-MeSO2-DDE) and the anticancer drug o,p′-DDD (mitotane) were studied in Göttingen minipigs. The animals were given 3-MeSO2-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-MeSO2-DDE. o,p′-DDD plasma concentrations declined rapidly to low levels during 4 days. 3-MeSO2-DDE also decreased rapidly, but remained at high concentrations throughout the study. In fat, 3-MeSO2-DDE reached about 25-fold higher levels than o,p′-DDD at 30 days, and both substances were eliminated slowly from this tissue. 3-MeSO2-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-MeSO2-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.

Ort, förlag, år, upplaga, sidor
2008. Vol. 61, nr 2, s. 267-274
Nyckelord [en]
3-MeSO2-DDE, Adrenal cortex, Minipig, Mitotane, o, p′-DDD, Pharmacokinetics
Nationell ämneskategori
Medicin och hälsovetenskap Biologiska vetenskaper
Identifikatorer
URN: urn:nbn:se:uu:diva-96122DOI: 10.1007/s00280-007-0468-xISI: 000251009400009PubMedID: 17431626OAI: oai:DiVA.org:uu-96122DiVA, id: diva2:170594
Tillgänglig från: 2007-09-06 Skapad: 2007-09-06 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. Adrenocorticolysis Induced by 3-MeSO2-DDE: Mechanisms of Action, Kinetics and Species Differences
Öppna denna publikation i ny flik eller fönster >>Adrenocorticolysis Induced by 3-MeSO2-DDE: Mechanisms of Action, Kinetics and Species Differences
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2007. s. 52
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 331
Nyckelord
Toxicology, 3-methylsulphonyl-DDE, o, p'-DDD, CYP11B1, adrenal cortex, tissue-specific toxicity, bioactivation, kinetics, Y-1 cells, Toxikologi
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:uu:diva-8180 (URN)978-91-554-6950-4 (ISBN)
Disputation
2007-09-29, Lindahlsalen, Evolutionsbiologiskt centrum (EBC), Norbyvägen 18 A, Uppsala, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2007-09-06 Skapad: 2007-09-06 Senast uppdaterad: 2011-01-20Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltextPubMed

Personposter BETA

Brandt, Ingvar

Sök vidare i DiVA

Av författaren/redaktören
Brandt, Ingvar
Av organisationen
Ekotoxikologi
I samma tidskrift
Cancer Chemotherapy and Pharmacology
Medicin och hälsovetenskapBiologiska vetenskaper

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetricpoäng

doi
pubmed
urn-nbn
Totalt: 632 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf