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The Suggested Physiologic Aryl Hydrocarbon Receptor Activator and Cytochrome P4501 Substrate 6-Formylindolo[3,2-b]carbazole Is Present in Humans
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Analytical Chemistry.
Institute of Environmental Medicine, Karolinska Institute.
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2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 5, 2690-2696 p.Article in journal (Refereed) Published
Abstract [en]

Dioxins and other polycyclic aromatic compounds formed during the combustion of waste and fossil fuels represent a risk to human health, as well as to the well being of our environment. Compounds of this nature exert carcinogenic and endocrine disrupting effects in experimental animals by binding to the orphan aryl hydrocarbon receptor (AhR). Understanding the mechanism of action of these pollutants, as well as the physiological role(s) of the AhR, requires identification of the endogenous ligand(s) of this receptor. We reported earlier that activation of AhR by ultraviolet radiation is mediated by the chromophoric amino acid tryptophan (Trp), and we suggested that a new class of compounds derived from Trp, in particular 6-formylindolo[3,2-b]carbazole (FICZ), acts as natural high affinity ligands for this receptor. Here we describe seven new FICZ-derived indolo[3,2-b]carbazole-6-carboxylic acid metabolites and two sulfoconjugates, and we demonstrate the following. (i) FICZ is formed efficiently by photolysis of Trp upon exposure to visible light. (ii) FICZ is an exceptionally good substrate for cytochromes P450 (CYP) 1A1, 1A2, and 1B1, and its hydroxylated metabolites are remarkably good substrates for the sulfotransferases (SULTs) 1A1, 1A2, 1B1, and 1E1. Finally,(iii) sulfoconjugates of phenolic metabolites of FICZ are present in human urine. Our findings indicate that formylindolo[3,2-b]carbazols are the most potent naturally occurring activators ofthe AhR signaling pathway and may be the key substrates of the CYP1 and SULT1 families of enzymes. These conclusions contradict the wide spread view that xenobiotic compounds are the major AhR ligands and CYP1 substrates.

Place, publisher, year, edition, pages
2009. Vol. 284, no 5, 2690-2696 p.
URN: urn:nbn:se:su:diva-38268ISI: 000262700900011OAI: diva2:308513
Available from: 2010-04-06 Created: 2010-04-06 Last updated: 2010-04-22Bibliographically approved
In thesis
1. Novel Solid Phase Extraction and Mass Spectrometry Approaches to Multicomponent Analyses in Complex Matrices
Open this publication in new window or tab >>Novel Solid Phase Extraction and Mass Spectrometry Approaches to Multicomponent Analyses in Complex Matrices
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Analysis of compounds present in complex matrices is always a challenge, which can be partly overcome by applying various sample preparation techniques prior to detection. Ideally, the extraction techniques should be as selective as possible, to minimize the concentration of interfering substances. In addition, results can be improved by efficient chromatographic separation of the sample components. The elimination of interfering substances is especially important when utilizing mass spectrometry (MS) as a detection technique since they influence the ionization yields. It is also important to optimize ionization methods in order to minimize detection limits.

In the work this thesis is based upon, selective solid phase extraction (SPE) materials, a restricted access material (RAM) and graphitized carbon black (GCB) were employed for clean up and/or pre-concentration of analytes in plasma, urine and agricultural drainage water prior to liquid chromatography/mass spectrometry (LC/MS). Two SPE formats, in which GCB was incorporated in µ-traps and disks, were developed for cleaning up small and large volume samples, respectively. In addition, techniques based on use of sub-2 µm C18 particles at elevated temperatures and a linear ion trap (LIT) mass spectrometer were developed to improve the efficiency of LC separation and sensitivity of detection of 6-formylindolo[3,2-b]carbazole (FICZ) metabolites in human urine.

It was also found that GCB can serve not only as a SPE sorbent, but also as a valuable surface for surface-assisted laser desorption ionization (SALDI) of small molecules. The dual functionality of GCB was utilized in a combined screening-identification/quantification procedure for fast elimination of negative samples. This may be particularly useful when processing large numbers of samples. SALDI analyses of small molecules was further investigated and improved by employing two kinds of new surfaces: oxidized GCB nanoparticles and silicon nitride.

Place, publisher, year, edition, pages
Stockholm: Department of Analytical Chemistry, Stockholm University, 2010. 62 p.
Sample preparation, SPE, RAM, GCB µ-trap, GCB disk, High temperature LC, LC/MS, ESI, APCI, Matrix effects, LIT-MS, SALDI, Sample screening, Oxidized GCB, Silicon nitride
National Category
Analytical Chemistry
Research subject
Analytical Chemistry
urn:nbn:se:su:diva-38625 (URN)978-91-7447-050-5 (ISBN)
Public defence
2010-06-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Available from: 2010-05-11 Created: 2010-04-22 Last updated: 2010-05-04Bibliographically approved

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Wincent, EmmaAmini, NahidRannug, Ulf
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