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  • 1. Berg, Ingrid
    et al.
    Neumann, Rita
    Cederberg, Håkan
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Jeffreys, Alec J
    Two modes of germline instability at human minisatellite MS1 (locus D1S7): complex rearrangements and paradoxical hyperdeletion.2003In: Am J Hum Genet, ISSN 0002-9297, Vol. 72, no 6, p. 1436-47Article in journal (Refereed)
    Abstract [en]

    Minisatellite MS1 (locus D1S7) is one of the most unstable minisatellites identified in humans. It is unusual in having a short repeat unit of 9 bp and in showing somatic instability in colorectal carcinomas, suggesting that mitotic replication or repair errors may contribute to repeat-DNA mutation. We have therefore used single-molecule polymerase chain reaction to characterize mutation events in sperm and somatic DNA. As with other minisatellites, high levels of instability are seen only in the germline and generate two distinct classes of structural change. The first involves large and frequently complex rearrangements that most likely arise by recombinational processes, as is seen at other minisatellites. The second pathway generates primarily, if not exclusively, single-repeat changes restricted to sequence-homogeneous regions of alleles. Their frequency is dependent on the length of uninterrupted repeats, with evidence of a hyperinstability threshold similar in length to that observed at triplet-repeat loci showing expansions driven by dynamic mutation. In contrast to triplet loci, however, the single-repeat changes at MS1 exclusively involve repeat deletion, and can be so frequent--as many as 0.7-1.3 mutation events per sperm cell for the longest homogeneous arrays--that alleles harboring these long arrays must be extremely ephemeral in human populations. The apparently impossible existence of alleles with deletion-prone uninterrupted repeats therefore presents a paradox with no obvious explanation.

  • 2. Bergander, Linda
    et al.
    Wincent, Emma
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rannug, Agneta
    Foroozesh, Maryam
    Alworth, William
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Metabolic fate of the Ah receptor ligand 6-formylindolo[3,2-b]carbazole2004In: Chemico-Biological Interactions, ISSN 0009-2797, Vol. 149, no 2-3, p. 151-164Article in journal (Refereed)
    Abstract [en]

    The physiological role of the aryl hydrocarbon receptor (AhR), a member of the basic helix-loop-helix PER-ARNT-SIM (PAS) transcription factor family is not known. We have suggested that the AhR is involved in light signaling through binding of photoproducts with high AhR affinity. This suggestion is based on (i) the high AhR affinity of the tryptophan photoproduct formylindolo[3,2-b]carbazole (FICZ), (ii) the induction of rapid and transient expression of AhR-regulated genes by FICZ and by extracts of UV-irradiated tryptophan as well as (iii) the fact that light induces the AhR-regulated cytochrome P450s CYP1A1, CYP1B1 and CYP2S1. The transient mRNA expression caused by light and tryptophan photoproducts suggests that the biotransformation enzymes induced by AhR activation take part in a metabolic degradation of the natural AhR ligand. This study aimed at identifying the involvement of phase I and phase II enzymes in the metabolic degradation of FICZ. A cytochrome P450-dependent metabolism of FICZ giving rise to preferentially mono- and di-hydroxylated derivatives has earlier been reported. In the present study, rat and human hepatic S9 mixes were employed together with specific enzyme inhibitors and cofactors. Compared to the Aroclor-induced rat liver S9, the non-induced rat liver S9 and the human liver S9 caused a more complex metabolite profile of FICZ. The CYP1A1 enzyme was confirmed to be the most important enzyme for the first step in the metabolism. CYP1A2 was found to have overlapping specificity with CYP1A1 being able to form the same major metabolites although with different kinetics. CYP1B1 turned out to be preferentially involved in the further metabolism of dihydroxylated metabolites. Microsomal epoxide hydrolase, and as yet not identified forms of sulphotransferases and glucuronosyltransferases were also found to take part in the metabolic degradation of FICZ. Thus, tryptophan photoproducts fit into a model in which the ligand-activated AhR signaling is autoregulated by the induced metabolic enzymes.

  • 3.
    Bergander, Linda
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Öberg, Mattias
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Håkansson, Helene
    Rannug, Agneta
    Identification of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole in cell culture medium, as a factor that controls the constitutive aryl hydrocarbon receptor activity2005In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 85, no 2, p. 935-943Article in journal (Refereed)
    Abstract [en]

    The presence of high affinity ligands for the aryl hydrocarbon receptor (AhR) in cell culture medium has generally been overlooked. Such compounds may confound mechanistic studies of the important AhR regulatory network. Numerous reports have described that light exposed cell culture medium induces AhR-dependent activity. In this study, we aimed at identifying the causative substance(s). A three-dimensional factorial design was used to study how the background activity of CYP1A1 in a rat hepatoma cell line (MH1C1) was controlled by photoproducts formed in the medium exposed to normal laboratory light. The light induced activity was found to be tryptophan dependent, but independent of riboflavin and other components in the medium. The light exposed medium showed the same transient enzyme inducing activity in vitro as the AhR ligand 6-formylindolo[3,2-b]carbazole (FICZ). This substance, which we have previously identified as being formed in UV-exposed tryptophan solutions, is a substrate for CYP1A1 and it has a higher AhR binding affinity than TCDD. Several tryptophan related photoproducts were detected in the light-exposed medium. For the first time one of the formed photoproducts was identified as FICZ with bioassay driven fractionation coupled with HPLC/MS. These results clearly show that tryptophan derived AhR ligands, which have been suggested to be endogenous AhR ligands, influence the background levels of CYP1A1 activity in cells in culture.

  • 4. Bergknut, Magnus
    et al.
    Kucera, Adam
    Frech, Kristina
    Andersson, Erika
    Engwall, Magnus
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Koci, Vladimir
    Andersson, Patrik L
    Haglund, Peter
    Tysklind, Mats
    Identification of potentially toxic compounds in complex extracts of environmental samples using gas chromatography-mass spectrometry and multivariate data analysis.2007In: Environ Toxicol Chem, ISSN 0730-7268, Vol. 26, no 2, p. 208-17Article in journal (Other academic)
  • 5. Cederberg, Håkan
    et al.
    Rannug, Ulf
    Stockholm University.
    Mechanisms of human minisatellite mutation in yeast.2006In: Mutat Res, ISSN 0027-5107, Vol. 598, no 1-2, p. 132-43Article in journal (Other academic)
  • 6. Janosik, Tomasz
    et al.
    Rannug, Agneta
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wahlström, Niklas
    Slätt, Johnny
    Bergman, Jan
    Chemistry and Properties of Indolocarbazoles2018In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 118, no 18, p. 9058-9128Article, review/survey (Refereed)
    Abstract [en]

    The indolocarbazoles are an important class of nitrogen heterocycles which has evolved significantly in recent years, with numerous studies focusing on their diverse biological effects, or targeting new materials with potential applications in organic electronics. This review aims at providing a broad survey of the chemistry and properties of indolocarbazoles from an interdisciplinary point of view, with particular emphasis on practical synthetic aspects, as well as certain topics which have not been previously accounted for in detail, such as the occurrence, formation, biological activities, and metabolism of indolo[3,2-b]carbazoles. The literature of the past decade forms the basis of the text, which is further supplemented with older key references.

  • 7.
    Kamat, Nasir
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Khidhir, Mohammed A.
    Alashari, Mouied M.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Microsatellite instability and loss of heterozygosity detected in middle-aged patients with sporadic colon cancer: A retrospective study2013In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 6, no 5, p. 1413-1420Article in journal (Refereed)
    Abstract [en]

    Microsatellite instability (MSI) is a mutator phenotype that results from a defective mismatch repair (MMR) pathway. The present study examined the incidence of MSI and loss of heterozygosity (LOH) according to five markers from the panel of the National Cancer Institute (NCI) in 38 colorectal cancer (CRC) patients from the United Arab Emirates (UAE). MSI and LOH were analyzed using fragment analyses in a multiplex PCR setting on a capillary array electrophoresis platform. The expression of the MMR proteins, hMLH1 and hMSH2, was analyzed using immunohistochemistry. The cohort consisted of 17 females (44.7%) and 21 males (55.3%) with mean ages of 59.9 and 63.3 years, respectively. The overall MSI incidence was 31.3% (95% CI, 16.1-50.0), and included three patients with high MSI (MSI-H; 9.4%; 95% CI, 2.0-25.0) and seven patients with low MSI (MSI-L; 21.9%; 95% CI, 10.7-39). LOH was detected in three patients, while the remaining 25 patients (65.8%) showed no instability and were therefore classified as microsatellite stable (MSS). MSI was detected in the following screened markers: Bat25 in seven patients, Bat26 in three patients, adenomatous polyposis coli (APC; D5S346) in five patients, AFM093xh3 (D2S123) in two patients and Mfd15 (D17S250) in three patients. Of the five MSI-positive patients, four (80%) were evidently younger, aged 38, 48, 49 and 59 years, respectively. The MSI-H incidence (9.4%) was lower compared with that of other ethnic groups. In terms of the MMR proteins, hMLH1 expression was deficient in seven patients, of whom three were MSI-H patients, and hMSH2 was deficient in three patients. Fisher's exact test showed significant associations between hMLH1 and MSI when classified as MSS, MSI-L or MSI-H (P=0.0003). No such association was observed with abnormal MMR protein expression, age, cancer stage or gender.

  • 8.
    Kamat, Nasir
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Khidhir, Mohammed A.
    Hussain, Sabir
    Alashari, Mouied M.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients2014In: Cancer Cell International, ISSN 1475-2867, E-ISSN 1475-2867, Vol. 14, p. 118-Article in journal (Refereed)
    Abstract [en]

    Background: The inevitable side effects of the currently used chemotherapy are associated with serious syndromes. Genotoxic effects and consequent genetic instability may play an important role in these syndromes. The aim of the study was to evaluate chemotherapy-related microsatellite instability (MSI), loss of heterozygosity (LOH), and loss of mismatch repair (MMR) expression in solid tumor patients. Methods: Samples were collected from 117 de novo patients with solid tumors of different origins. Specimens, taken pre- and post-treatment, were screened for MSI and LOH in 10 microsatellite sequences in blood, and expression of five MMR proteins were analyzed in cancer tissues using immunohistochemistry. Statistical analysis included the use of; Fisher's exact test, Chi Square, and an inter-rater reliability test using Cohen's kappa coefficient. Results: Microsatellite analysis showed that 66.7% of the patients had MSI, including 23.1% high-positive MSI and 43.6% low-positive MSI. A large portion (41%) of the patients exhibited LOH in addition to MSI. MSI and LOH were detected in seven loci in which incidence rates ranged from 3.8% positive for Bat-26 to 34.6% positive for Tp53-Alu. Immunohistochemistry revealed that human mutL homolog 1 (hMLH1) expression was deficient in 29.1% of the patients, whereas 18.8%, 23.9%, 13.4%, and 9.7% were deficient for human mutS homolog 2 (hMSH2), P53, human mutS homolog 6 (hMSH6) and human post-meiotic segregation increased 2 (hPMS2), respectively. There was a significant correlation between MSI and LOH incidence in Tp53-Alu, Mfd41, and APC with low or deficient expression of hMLH1, hMSH2, and P53. A significant association between MSI and LOH, and incidence of secondary tumors was also evident. Conclusions: The negative correlation between MMR expression, MSI, and LOH and increased resistance to anti-cancer drugs and development of secondary cancers demonstrates a useful aid in early detection of potential chemotherapy-related side-effects. The diagnostic value demonstrated in our earlier study on breast cancer patients was confirmed for other solid tumors.

  • 9.
    Kamat, Nasir
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Khidhir, Mohammed A.
    Jaloudi, Mohammed
    Hussain, Sabir
    Alashari, Mouied M.
    Al Qawasmeh, Khaled H.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    High incidence of microsatellite instability and loss of heterozygosity in three loci in breast cancer patients receiving chemotherapy: a prospective study2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 373-Article in journal (Refereed)
    Abstract [en]

    Background: The aim of the study was to evaluate potential chemotherapy-induced microsatellite instability, loss of heterozygosity, loss of expression in mismatch repair proteins and associations with clinical findings in breast cancer patients, especially resistance to chemotherapy and/or development of other tumors in the four years following chemotherapy treatment. Methods: A comprehensive study of chemotherapy-related effects with a follow-up period of 48 months post treatment was conducted. A total of 369 peripheral blood samples were collected from 123 de novo breast cancer patients. Microsatellite instability and loss of heterozygosity in five commonly used marker loci (including Tp53-Alu of the tumor suppressor gene TP53) were analyzed in blood samples. Sampling was conducted on three occasions; 4-5 weeks prior to the first chemotherapy session (pre-treatment), to serve as a baseline, followed by two consecutive draws at 12 weeks intervals from the first collection. Mismatch repair protein expression was evaluated in cancer tissues using immunohistochemistry for three mismatch-repair related proteins. Results: A total of 70.7% of the patients showed microsatellite instability for at least one locus, including 18.6% marked as high-positive and 52.1% as low-positive; 35.8% showed loss of heterozygosity in addition to microsatellite instability, while 29.3% exhibited microsatellite stability. The following incidence rates for microsatellite instability and loss of heterozygosity were detected: 39.1% positive for Tp53-Alu, 31.1% for locus Mfd41, and 25.3% for locus Mfd28. A higher occurrence of loss of heterozygosity was noted with alleles 399 and 404 of Tp53-Alu. The mismatch repair protein expression analysis showed that the chemotherapy caused a loss of 29.3% in hMLH1 expression, and 18.7% and 25.2% loss in hMSH2 and P53 expression, respectively. A strong correlation between low or deficient hMSH2 protein expression and occurrence of mismatch repair/loss of heterozygosity events in Mfd41, Tp53-Alu, and Mfd28 was evident. A significant association between mismatch repair/loss of heterozygosity and incidence of secondary tumors was also established. Conclusion: Our results suggest that microsatellite instability, loss of heterozygosity, and deficiency in mismatch repair may serve as early prognostic factors for potential chemotherapy-related side effects in breast cancer patients.

  • 10.
    Kamat, Nasir
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Khidhir, Mohammed
    Management of Natural Conservation , UAE.
    Hussain, Sabir
    Oncology department, Tawam Hospital, UAE.
    Alashari, Mouied
    Pathology Department, Tawam hospital, UAE.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patientsManuscript (preprint) (Other academic)
    Abstract [en]

    Objectives: The aim of the studywas to evaluate chemotherapy-related microsatellite instability (MSI), loss of heterozygosity (LOH), and loss of mismatch repair (MMR) expression in solid tumor patients. Methods: Samples were collected from 117 de novo patients with solid tumors of different origins. Specimens, taken pre- and post-treatment, were screened for MSI and LOH in 10 microsatellite sequences in blood, and expression of five MMR proteins were analyzed in cancer tissues using immunohistochemistry. Results: Microsatellite analysis showed that 66.7% of the patients had MSI, including 23.1% high-positive MSI and 43.6% low-positive MSI. A large portion (41%) of the patients exhibited LOH in addition to MSI. MSI and LOH were detected in seven loci in which incidence rates ranged from 3.8% positive for Bat-26 to 34.6% positive for Tp53-Alu. Immunohistochemistry revealed that human mutL homolog 1 (hMLH1) expression was deficient in 29.1% of the patients, whereas18.8%, 23.9%, 13.4%, and 9.7% were deficient for human mutS homolog 2(hMSH2), P53, human mutS homolog 6 (hMSH6) and human post-meiotic segregation increased 2 (hPMS2), respectively. There was a significant correlation between MSI and LOH incidence in Tp53-Alu, Mfd41, and APC with low or deficient expression of hMLH1, hMSH2, and P53. A significant association between MSI and LOH, and incidence of secondary tumors was also evident. Conclusions: The negative correlation between MMR expression, MSI, and LOH and increased resistance to anti-cancer drugs and development of secondary cancers demonstrates a useful aid in early detection of potential chemotherapy-related side-effects. The diagnostic value demonstrated in our earlier study on breast cancer patients was confirmed for other solid tumors.

  • 11. Luecke, S.
    et al.
    Wincent, E.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Backlund, M.
    Rannug, U.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rannug, A.
    Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappa B2010In: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 184, no 3, p. 466-473Article in journal (Refereed)
    Abstract [en]

    UVB induces the expression of genes controlled by the aryl hydrocarbon receptor (AhR). a transcription factor that has been implicated in the UV stress response. In this study, we used the human hepatoma cell line HepG2 to investigate in more detail the effects of UVB irradiation on AhR activation and induction of cytochrome P450 1A1 (CYP1A1), a highly AhR-responsive gene. The CYP1A1 enzyme efficiently degrades 6-formylindolo[3,2-b]carbazole (FICZ), a high affinity ligand and suggested endogenous activator of the AhR. We show that physiologically relevant doses of UVB suppress CYP1A1 gene expression immediately after irradiation, but induce its expression later in an AhR-dependent manner. The initial repression phase of CYP1A1 transcription was mediated by another UVB-inducible transcription factor, the nuclear factor kappa B (NF kappa B). Crosstalk between AhR and NF kappa B signaling has earlier been implicated to control CYP1A1 expression following stimulation by xenobiotics and cytokines. Now, our findings clearly indicate a role of NF kappa B also in UVB-dependent AhR signaling. We also observed that UVB reduced the catalytic activity of the CYP1A1 enzyme. Thereby. UVB attenuated the clearance of FICZ, which led to prolonged AhR activation. We further noted that repeated irradiation with UVB or H2O2 treatment shifted the cells into a refractory state in which AhR signaling could not be efficiently activated by UVB or H2O2, but by ligands. Together, our results suggest that the NF kappa B-mediated initial suppression of CYP1A1 as well as the unresponsiveness of AhR signaling to repeated irradiation may be part of a protective cellular UV stress response.

  • 12.
    Masala, Silvia
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Pressurized liquid extraction as an alternative to the Soxhlet extraction procedure stated in the US EPA method TO-13A for the recovery of polycyclic aromatic hydrocarbons adsorbed on polyurethane foam plugs2014In: Analytical Methods, ISSN 1759-9660, E-ISSN 1759-9679, Vol. 6, no 20, p. 8420-8425Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to develop a pressurized liquid extraction (PLE) method as an alternative to the relatively time consuming Soxhlet extraction procedure described in the United States Environmental Protection Agency (US EPA) method TO-13A for the extraction of PAHs adsorbed onto polyurethane foam plugs (PUFs). For this purpose PUF air samples were collected and split into two parts: one part extracted using PLE and the other one using Soxhlet extraction. Comparable PAH concentrations were obtained upon analysis of the extracts showing that the PLE method developed in this work is a more convenient choice than the commonly used Soxhlet extraction technique proposed by US EPA for the determination of PAHs in air samples. In fact, the developed PLE method required shorter assay times (minutes versus hours), less solvent consumption and simpler operational methods. The exhaustiveness of the developed PLE method was evaluated using repeat static extraction cycles, demonstrating an extraction efficiency for the PAHs of greater than 99%. The PLE method was then applied to diesel exhaust and wood smoke PUF samples showing an extraction efficiency for the PAHs of greater than 93% and 96%, respectively. Furthermore, a PLE method for PUF cleaning was developed as well and employed as an alternative to Soxhlet extraction. The PLE methods developed for cleaning and extracting PUFs presented in this work are suitable to be used in mutagenicity studies using the Ames Salmonella assay as no mutagenicity was found in the PLE generated blanks

  • 13. Mohammadi-Bardbori, Afshin
    et al.
    Bengtsson, Johanna
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rannug, Agneta
    Wincent, Emma
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Quercetin, Resveratrol, and Curcumin Are Indirect Activators of the Aryl Hydrocarbon Receptor (AHR)2012In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 25, no 9, p. 1878-1884Article in journal (Refereed)
    Abstract [en]

    Several polyphenols have been shown to activate the aryl hydrocarbon receptor (AHR) in spite of the fact that they bind to the receptor with low affinity. The aim of this study was to investigate whether quercetin (QUE), resveratrol (RES), and curcumin (CUR) interfere with the metabolic degradation of the suggested endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ) and thereby indirectly activate the AHR. Using recombinant human enzyme, we confirmed earlier reported inhibitory effects of the polyphenols on cytochrome P4501A1 (CYP1A1) activity, and inhibition of metabolic clearance of FICZ was documented in FICZ-treated immortalized human keratinocytes (HaCaT). CYP1A1 activity was induced in HaCaT cells by all three compounds, and when they were added together with FICZ, a prolonged activation was observed after a dose-dependent inhibition period. The same pattern of responses was seen at the transcriptional level as determined with a CYP1A1 reporter assay in human liver hepatoma (HepG2) cells. To test the ability of the polyphenols to activate the AHR in the absence of FICZ, the cells were treated in medium, which in contrast to commercial batches of medium did not contain background levels of FICZ. Importantly, AHR activation was only observed in the commercial medium. Taken together, these findings suggest that QUE, RES, and CUR induce CYP1A1 in an indirect manner by inhibiting the metabolic turnover of FICZ. Humans are exposed to these compounds through the diet and nutritional supplements, and we propose that altered systemic levels of FICZ caused by such compounds may have physiological consequences.

  • 14. Mohammadi-Bardbori, Afshin
    et al.
    Vikström Bergander, Linda
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Rannug, Agneta
    NADPH Oxidase-Dependent Mechanism Explains How Arsenic and Other Oxidants Can Activate Aryl Hydrocarbon Receptor Signaling2015In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 12, p. 2278-2286Article in journal (Refereed)
    Abstract [en]

    The mechanisms explaining arsenic toxicity are not well understood, but physiological consequences of stimulated aryl hydrocarbon receptor (AHR) signaling both directly and through cross-talk with other pathways have been indicated. The aim of this study was to establish how arsenic interacts with AHR-mediated transcription. The human hepatoma cell line (HepG2-XRE-Luc) carrying a luciferase reporter under the control of two AHR response elements (AHREs) and immortalized human keratinocytes (HaCaT) were exposed to sodium arsenite (NaAsO2; As3+), alone or in combination with the endogenous high affinity AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ). Luciferase activity, cytochrome P4501A1 (CYP1A1) activity, oxidative stress-related responses, metabolic clearance of FICZ, and NADPH:oxidase (NOX) activity as well as nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent gene expression were measured. Arsenic inhibited,CYP1A1 enzyme activity and reduced the metabolic clearance of FICZ. Arsenic also led to activated CYP1A1 transcription but only in cells grown in medium containing trace amounts of the endogenous ligand FICZ, pointing to an indirect mechanism of activation. Initially, arsenic caused dose-dependent inhibition of FICZ-activated AHR signaling, disturbed intracellular GSH status, and increased expression of oxidative stress-related genes. Silencing of NOX4, addition of N-acetylcystein, or pretreatment with arsenic itself attenuated the initial dose-dependent inhibition of AHR signaling. Arsenic pretreatment led to elevated GSH levels and sensitized the cells to ligaild-dependent AHR signaling, while silencing of Nrf2 significantly reduced arsenic-mediated, activation of the AHR. In addition, influence of NOX on AHR activation was also observed in cells treated with the SH-reactive metals cadmium, mercury, and nickel. Together, the results suggest that SH-reactive agents via a new and possibly general NOX/H2O2-dependent mechanism can interfere with the endogenous regulation of the AHR.

  • 15. Rannug, Agneta
    et al.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation2018In: Critical reviews in toxicology, ISSN 1040-8444, E-ISSN 1547-6898, Vol. 48, no 7, p. 555-574Article, review/survey (Refereed)
    Abstract [en]

    The aryl hydrocarbon receptor (AHR) is not essential to survival, but does act as a key regulator of many normal physiological events. The role of this receptor in toxicological processes has been studied extensively, primarily employing the high-affinity ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, regulation of physiological responses by endogenous AHR ligands remains to be elucidated. Here, we review developments in this field, with a focus on 6-formylindolo[3,2-b]carbazole (FICZ), the endogenous ligand with the highest affinity to the receptor reported to date. The binding of FICZ to different isoforms of the AHR seems to be evolutionarily well conserved and there is a feedback loop that controls AHR activity through metabolic degradation of FICZ via the highly inducible cytochrome P450 1A1. Several investigations provide strong evidence that FICZ plays a critical role in normal physiological processes and can ameliorate immune diseases with remarkable efficiency. Low levels of FICZ are pro-inflammatory, providing resistance to pathogenic bacteria, stimulating the anti-tumor functions, and promoting the differentiation of cancer cells by repressing genes in cancer stem cells. In contrast, at high concentrations FICZ behaves in a manner similar to TCDD, exhibiting toxicity toward fish and bird embryos, immune suppression, and activation of cancer progression. The findings are indicative of a dual role for endogenously activated AHR in barrier tissues, aiding clearance of infections and suppressing immunity to terminate a vicious cycle that might otherwise lead to disease. There is not much support for the AHR ligand-specific immune responses proposed, the differences between FICZ and TCDD in this context appear to be explained by the rapid metabolism of FICZ.

  • 16.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Background and description of formylindolo[3,2-b]carbazoles2007Conference paper (Other (popular science, discussion, etc.))
  • 17.
    Sadiktsis, Ioannis
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Nilsson, Gertrud
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Camfil AB, Research and Development Department, Sweden.
    Johansson, Ulf
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Westerholm, Roger
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Removal of polycyclic aromatic hydrocarbons and genotoxic compounds in urban air using air filter materials for mechanical ventilation in buildings2016In: Science and Technology for the Built Environment, ISSN 2374-474X, Vol. 22, no 3, p. 346-355Article in journal (Refereed)
    Abstract [en]

    Humans spend most of their lives in indoor environments; hence, indoor exposure to air pollution may constitute a large part of the total exposure to air pollution. Polycyclic aromatic hydrocarbons are well known for their mutagenicity and carcinogenicity and are ubiquitous in urban environments as a result of combustion from e.g. vehicular traffic. Polycyclic aromatic hydrocarbons associated to air particulate matter in indoor environments originates from several sources including: cooking and heating, outdoor sources, smoking, candle and incense burning. Infiltration has been suspected to be one major source of indoor polycyclic aromatic hydrocarbons. In this study, four different air filter materials intended for mechanical ventilation were tested for their capability to remove particle bound polycyclic aromatic hydrocarbons and other genotoxic compounds from a real urban aerosol. Particles were sampled at two highly trafficked locations in Stockholm using a sampling system capable of sample particles in parallel, thus allowing sampling of filtered and un-filtered air simultaneously. The sampled particles were extracted and analysed for polycyclic aromatic hydrocarbons and the genotoxicity of the organic extract was determined using Ames mutagenicity tests. Each air filters capability of removing polycyclic aromatic hydrocarbons and reducing genotoxic effects was determined by comparing the filtered and un-filtered air samples. The results showed that all air filter materials had the capability of removing polycyclic aromatic hydrocarbons and reduce genotoxic effects downstream the air filter, and that the magnitude of the reduction was correlated with the standardized particulate collection efficiencies of a 0.4 μm particles for the tested air filter materials. However, the filter with the lowest performance did not significantly reduce direct acting mutagens.

  • 18.
    Smirnova, Anna
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wincent, Emma
    Vikström Bergander, Linda
    Alsberg, Tomas
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Bergman, Jan
    Rannug, Agneta
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evidence for New Light-Independent Pathways for Generation of the Endogenous Aryl Hydrocarbon Receptor Agonist FICZ2016In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 29, no 1, p. 75-86Article in journal (Refereed)
    Abstract [en]

    Activation of the aryl hydrocarbon receptor (AhR), a conserved transcription factor best known as a target for highly toxic halogenated substances such as dioxin, under normal xenobiotic-free conditions is of considerable scientific interest. We have demonstrated previously that a photoproduct of tryptophan, 6-formylindolo[3,2-b]carbazole (FICZ), fulfills the criteria for an endogenous ligand for this receptor and proposed that this compound is the enigmatic mediator of the physiological functions of AhR. Here, we describe novel light-independent pathways by which FICZ can be formed. The oxidant H2O2 was shown to convert tryptophan to FICZ on its own in the absence of light. The enzymatic deamination of tryptamine yielded indole-3-acetaldehyde (I3A), which then rearranged to FICZ and its oxidation product, indolo[3,2-b]carbazole-6-carboxylic acid (CICZ). Indole-3-pyruvate (I3P) also produced I3A, FICZ, and CICZ. Malassezia yeast species, which constitute a part of the normal skin microbiota, produce a number of AhR activators from tryptophan. We identified both FICZ and CICZ among those products. Formation of FICZ from tryptophan or I3P produces a complex mixture of indole derivatives, some of which are CYP1A1 inhibitors. These can hinder the cellular clearance of FICZ and thereby increase its power as an AhR agonist. We present a general molecular mechanism involving dehydrogenations and oxidative coupling for the formation of FICZ in which I3A is the important precursor. In conclusion, our results suggest that FICZ is likely to be formed systemically.

  • 19.
    Wincent, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Amini, Nahid
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Luecke, Sandra
    Glatt, H.
    Bergman, Jan
    Crescenzi, Carlo
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Rannug, Agneta
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans2009In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 5, p. 2690-2696Article in journal (Refereed)
    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 of the AhR signaling pathway and may be the key substrates of the CYP1 and SULT1 families of enzymes. These conclusions contradict the widespread view that xenobiotic compounds are the major AhR ligands and CYP1 substrates.

  • 20.
    Wincent, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bengtsson, Johanna
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Bardbori, Afshin Mohammadi
    Alsberg, Tomas
    Stockholm University, Faculty of Science, Department of Applied Environmental Science (ITM).
    Luecke, Sandra
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Rannug, Agneta
    Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 12, p. 4479-4484Article in journal (Refereed)
    Abstract [en]

    Altered systemic levels of 6-formylindolo[3,2-b]carbazole (FICZ), an enigmatic endogenous ligand for the aryl hydrocarbon receptor (AHR), may explain adverse physiological responses evoked by small natural and anthropogenic molecules as well as by oxidative stress and light. We demonstrate here that several different chemical compounds can inhibit the metabolism of FICZ, thereby disrupting the autoregulatory feedback control of cytochrome P4501 systems and other proteins whose expression is regulated by AHR. FICZ is both the most tightly bound endogenous agonist for the AHR and an ideal substrate for cytochrome CYP1A1/1A2 and 1B1, thereby also participating in an autoregulatory loop that keeps its own steady-state concentration low. At very low concentrations FICZ influences circadian rhythms, responses to UV light, homeostasis associated with pro-and anti-inflammatory processes, and genomic stability. Here, we demonstrate that, if its metabolic clearance is compromised, femtomolar background levels of this compound in cell-culture medium are sufficient to up-regulate CYP1A1 mRNA and enzyme activity. The oxidants UVB irradiation and hydrogen peroxide and the model AHR antagonist 3'-methoxy-4'-nitroflavone all inhibited induction of CYP1A1 enzyme activity by FICZ or 2,3,7,8-tetrachlorodibenzo-p-dioxin, thereby subsequently elevating intracellular levels of FICZ and activating AHR. Taken together, these findings support an indirect mechanism of AHR activation, indicating that AHR activation by molecules with low affinity actually may reflect inhibition of FICZ metabolism and raising questions about the reported promiscuity of the AHR. Accordingly, we propose that prolonged induction of AHR activity through inhibition of CYP1 disturbs feedback regulation of FICZ levels, with potential detrimental consequences.

  • 21.
    Wincent, Emma
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Shirani, Hamid
    Department of Bioscience and Nutrition, Karolinska Institute.
    Rannug, Ulf
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Janosik, Tomasz
    Department of Bioscience and Nutrition, Karolinska Institute.
    Synthesis and biological evaluation of fused thio- and selenopyrans as new indolocarbazole analogues with aryl hydrocarbon receptor affinity2009In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, Vol. 17, no 4, p. 1648-1653Article in journal (Refereed)
    Abstract [en]

    A series of thio- and selenopyrans having two fused indole units, structurally related to indolocarbazoles, have been prepared and evaluated for aryl hydrocarbon receptor (AhR) affinity, leading to the identification of several new significant AhR ligands. In particular, the parent thiopyrano[2,3-b:6,5-b′]diindole and its derivative having a methyl group in the central ring, as well as the two corresponding selenopyrans, displayed the highest potencies of the compounds tested.

1 - 21 of 21
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