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  • 1.
    Alm, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
    Andrén, Per E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, MMS, Medical Mass Spectrometry.
    Fex-Svenningsen, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expression in the neonatal mouse cerebral cortex2008In: Neurotoxicology, ISSN 0161-813X, E-ISSN 1872-9711, Vol. 29, no 4, p. 628-637Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs) are environmental contaminants found in human and animal tissues worldwide. Neonatal exposure to the flame retardant 2,2', 4,4',5-pentabromodiphenyl ether (PBDE-99) disrupts normal brain development in mice, and results in disturbed spontaneous behavior in the adult. The mechanisms underlying the late effects of early exposure are not clear. To gain insight into the initial neurodevelopmental damage inflicted by PBDE-99, we investigated the short-term effects of PBDE-99 on protein expression in the developing cerebral cortex of neonatal mice, and the cytotoxic and apoptotic effects of PBDE-99 in primary cultures of fetal rat cortical cells. We used two-dimensional difference gel electrophoresis (2D-DIGE) to analyze protein samples isolated from the cortex of NMRI mice 24h after exposure to a single oral dose of 12 mg/kg PBDE-99 on post-natal day 10. Protein resolution was enhanced by sample pre-fractionation. In the cell model, we determined cell viability using the trypan blue exclusion assay, and apoptosis using immunocytochemical detection of cleaved caspase-3. We determined the identity of 111 differentially expressed proteins, 32 (29%) of which are known to be cytoskeleton-related. Similar to previous findings in the striatum, we found elevated levels of the neuron growth-associated protein Gap43 in the cortex. In cultured cortical cells, a high concentration of PBDE-99 (30 microM) induced cell death without any apparent increase in caspase-3 activity. These results indicate that the permanent neurological damage induced by PBDE-99 during the brain growth spurt involve detrimental effects on cytoskeletal regulation and neuronal maturation in the developing cerebral cortex.

  • 2.
    Alm, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Fischer, Celia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Proteomic evaluation of neonatal exposure to 2,2,4,4,5-pentabromodiphenyl ether2006In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 114, no 2, p. 254-259Article in journal (Refereed)
    Abstract [en]

    Exposure to the brominated flame retardant 2,2 ,4,4 ,5-pentabromodiphenyl ether (PBDE-99) during the brain growth spurt disrupts normal brain development in mice and results in disturbed spontaneous behavior in adulthood. The neurodevelopmental toxicity of PBDE-99 has been reported to affect the cholinergic and catecholaminergic systems. In this study we use a proteomics approach to study the early effect of PBDE-99 in two distinct regions of the neonatal mouse brain, the striatum and the hippocampus. A single oral dose of PBDE-99 (12 mg/kg body weight) or vehicle was administered to male NMRI mice on neonatal day 10, and the striatum and the hippocampus were isolated. Using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE), we found 40 and 56 protein spots with significantly (p < 0.01) altered levels in the striatum and the hippocampus, respectively. We used matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-ToF-MS) to determine the protein identity of 11 spots from the striatum and 10 from the hippocampus. We found that the levels of proteins involved in neurodegeneration and neuroplasticity (e.g., Gap-43/neuromodulin, stathmin) were typically altered in the striatum, and proteins involved in metabolism and energy production [e.g., alpha-enolase; gamma-enolase; ATP synthase, H+ transporting, mitochondrial F1 complex, beta subunit (Atp5b); and alpha-synuclein] were typically altered in the hippocampus. Interestingly, many of the identified proteins have been linked to protein kinase C signaling. In conclusion, we identify responses to early exposure to PBDE-99 that could contribute to persistent neurotoxic effects. This study also shows the usefulness of proteomics to identify potential biomarkers of developmental neurotoxicity of organohalogen compounds.

  • 3.
    Alnuaimy, Ranin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Granskning av läkemedelsinformation i FASS gällande risk under graviditet och amning2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Bakgrund: År 1978 introduceras ett klassificeringssystem i FASS (Farmaceutiska specialiteter i Sverige) för att underlätta bedömningen vid förskrivning av läkemedel till gravida och ammande kvinnor. Detta gäller bedömningen av ett läkemedels risk för bieffekter under graviditet och amning utifrån vilken kategori det placeras i. När Sverige 1995 går med i EU beslutar den medicinska expertgruppen att inte längre granska FASS- texter utan lämna över uppgiften till själva läkemedelsföretagen. Syfte: I detta projektarbete jämförs FASS-texter under rubrikerna Graviditet och Amning med läkemedelskategorin som de är placerade i. Metod och Material: Läkemedelsprodukter som granskas i arbetet är totalt 422 produkter med indikationsområden för andningsorgan (ATC- grupp R) samt ögon och öron (ATC-grupp S). Läkemedelsgrupperna är intressanta eftersom de innehåller läkemedel som rekommenderas under graviditet samt amning som till exempel inhalationspreparat mot astma eller ögondroppar mot glaukom. De texter som granskas har hämtats från FASS hemsida www.fass.se. Ytterligare information såsom namn, form, styrka, beredningsform och tillverkare för läkemedlen har hämtats från NPL (Nationellt Produktregister för Läkemedel). Resultat: Studien visar att ca 5 % respektive 13 % av läkemedel inom indikationsområden Andningsorgan (ATC-grupp R) samt Ögon och Öron (ATC-grupp S) är felklassificerade i förhållande till kriterierna för en FASS-text. Procenten inkluderar även läkemedel med saknad klassificering. Diskussion: Eftersom granskning av FASS-texter inte sköts av någon myndighet längre är läkemedelsföretagen själva ansvariga för informationen som står i FASS idag. Detta har lett till problem i form av saknad klassificering eller fel klassificering av läkemedel i FASS-texter något som är viktigt ur graviditets- och amningsperspektiv. Problemet bör uppmärksammas av ansvariga läkemedelsföretag och kontrollmyndigheter.

  • 4.
    Andersson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Leaching of Pharmaceuticals in Soil Columns amended with Sludge2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Occurrence of pharmaceutical residues in surface and ground waters, used as a source for drinking water supply has been studied over the years. Wastewater treatment plants are generally not efficient enough to remove pharmaceuticals from wastewater and sewage sludge. As a result, they are released into the environment mainly via effluent discharges to surface water bodies, the reuse of biosolids in agriculture as soil amendment, and the disposal of biosolids to landfill areas.

    The aim of this study was to investigate the leaching behavior of pharmaceuticals from several therapeutic groups (i.e. atorvastatin, bicalutamide, carbamazepine, furosemide, hydrochlorothiazide, losartan, oxazepam, valsartan, and venlafaxine) using undisturbed soil columns (loamy sand, loam, and clay) and disturbed soil columns (till mixed with peat) amended with sewage sludge at laboratory-scale. The experiment was performed under controlled conditions to gain a better understanding of the leaching behavior of pharmaceuticals in the natural environment. Another objective was to single out the pharmaceuticals with the highest leaching potential (i.e. carbamazepine, hydrochlorothiazide, oxazepam, and valsartan) in order to analyze their effects on the environment based on earlier studies on the subject. Oxazepam, for example, has shown to have effects on fish such as increased feeding rate and activity.

    Leachate analysis show that, in general, pharmaceuticals leach slower in loamy sand compared to loam and clay which might be due to macro pores and funnel flow in the loamy and clayish soil which enhance the leaching rate. The accumulated mass (µg) in the leachate from clay (13) were also higher than in loam (5.7), loamy sand (2.6), and the till and peat (0) soil.  This indicates that the slow leaching of pharmaceuticals in loamy sand, and till and peat might enhance the sorption or degradation of pharmaceuticals compared to clay and loam.

  • 5.
    Andersson, Maria A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Petersson Grawé, Kierstin
    Karlsson, Oskar M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Abramsson-Zetterberg, Lilianne A-G
    Hellman, Björn E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Evaluation of the potential genotoxicity of chromium picolinate in mammalian cells in vivo and in vitro2007In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 45, no 7, p. 1097-1106Article in journal (Refereed)
    Abstract [en]

    Chromium picolinate (CrPic) is a synthetic nutritional supplement primarily used for weight loss and muscle building. Recent studies have indicated that CrPic might be genotoxic and these findings together with the wide-spread consumer use, have increased the concern about its safety. In the present study we investigated the potential genotoxicity of CrPic in mice given a single intraperitoneal injection (up to 3 mg/kg b.wt.) by evaluating the frequency of micronucleated polychromatic erythrocytes (fMNPCE) in peripheral blood, and DNA damage in lymphocytes and hepatocytes. The fMNPCE was evaluated after 42 h and DNA damage after 16 h. Using the Comet assay DNA damage was also monitored in extended-term cultures of human lymphocytes and in L5178Y mouse lymphoma cells that had been exposed for 3 h to 500 μM CrPic under different exposure conditions.

    A slight, but significant CrPic-induced increase in DNA damage (P < 0.001) was observed in the human lymphocytes, but only when these cells were exposed in the absence of serum. In all other experiments CrPic was found to be without genotoxic effects, both in vivo and in vitro. Taken together, our results suggest that a high concentration of CrPic might be DNA damaging, but only under non-physiological conditions.

  • 6.
    Andersson, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stenqvist, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Interindividual differences in initial DNA repair capacity when evaluating H2O2-induced DNA damage in extended-term cultures of human lymphocytes using the comet assay2007In: Cell Biology and Toxicology, ISSN 0742-2091, E-ISSN 1573-6822, Vol. 23, no 6, p. 401-411Article in journal (Refereed)
    Abstract [en]

    It has been suggested that extended-term cultures of human lymphocytes could be used as a complement to cell lines based on transformed cells when testing the genotoxicity of chemicals. To investigate whether the pattern of induced DNA damage and its subsequent repair differs significantly between cultures based on different blood donors, hydrogen peroxide (H2O2)-induced DNA damage was measured in cultures from four different subjects using the comet assay. The DNA damage was significantly increased in all cultures after 10 min exposure to 0.25 mmol/L H2O2, and there was a significant decrease in the H2O2-induced DNA damage in all cultures after 30 min of DNA repair. The level of damage varied between the different donors, especially after the repair. Using PCR and DNA sequencing, exon 5 of the p53 gene was sequenced in the lymphocytes from the donors with the lowest and highest residual damage. No such mutation was found. Mouse lymphoma L5178Y cells carrying the p53 mutation in exon 5 were included as a reference. These cells were found to be less sensitive toward the H2O2-induced DNA damage, and they were also found to have a rather low DNA repair capacity. The demonstrated variation in H2O2-induced DNA damage and DNA repair capacity between the cultures from the different subjects may be important from a risk assessment perspective, but is obviously not of decisive importance when it comes to the development of a routine assay for genotoxicity.

  • 7.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Induction of ethoxyresorufin O-deethylase (EROD) and endothelial activation of the heterocyclic amine Trp-P-1 in bird embryo hearts1998In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 72, no 7, p. 402-410Article in journal (Refereed)
    Abstract [en]

    The xenobiotic-metabolizing activity of avian heart was investigated in chicken and Eider duck embryos exposed to aryl hydrocarbon (Ah) receptor agonists in ovo. Both beta-naphthoflavone (BNF) and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) induced 7-ethoxyresorufin O-deethylase (EROD) activities in chicken embryo hearts whereas Eider duck embryos only responded to BNF. The differential responses of chicken and Eider duck embryos were used to examine the involvement of Ah receptor-mediated enzyme induction in the activation of the environmental and food mutagen 3-amino- 1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1). As determined by light microscopic autoradiography, there was a highly selective binding of non-extractable 3H-Trp-P-1-derived radioactivity in endothelial cells of large vessels and capillaries in hearts of BNF- and PCB 126-treated chicken embryos. No binding occurred at these sites in vehicle-treated controls. There was also a strong endothelial binding of 3H-Trp-P-1 in hearts of BNF-treated Eider duck embryos whereas no binding occurred in hearts of PCB 126-treated Eider duck embryos. A positive correlation between induction of EROD activity and covalent binding of 3H-Trp-P-1 to protein in heart homogenates from BNF- and PCB 126-treated chicken and Eider duck embryos was also observed. The results suggest a cytochrome P450 1A (CYP1A)-mediated activation of Trp-P-1 in avian heart endothelial cells although involvement of other Ah receptor-regulated enzymes is also possible. We propose that heart endothelial cells may be targets for bioactivation and toxicity of environmental contaminants in birds exposed to Ah receptor agonists.

  • 8.
    Annas, Anita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Granberg, Lena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Strandberg, William
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Brittebo, Eva B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Environmental Toxicology.
    Basal and induced EROD activity in the chorioallantoic membrane during chicken embryo development1999In: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 8, no 1, p. 49-52Article in journal (Other academic)
    Abstract [en]

    The chorioallantoic membrane (CAM) is a highly vascularized tissue that takes part in the respiratory exchange of gases through the eggshell. Although the CAM may be exposed to environmental contaminants, its response to pollutants has not been studied. We examined the cytochrome P4501A (CYP1A)-catalyzed deethylation of 7-ethoxyresorufin (EROD) in the CAM during chicken embryo development. EROD was constitutively present and was inducible by the aryl hydrocarbon (Ah) receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126). Our results suggest the CAM as a first line of defence of the avian embryo against toxic compounds, but also as a target for CYP1A-activated chemicals.

  • 9.
    Azarbayjani, Faranak
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Danielsson, Bengt R
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs?2002In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 43, no 5, p. 457-468Article in journal (Refereed)
    Abstract [en]

    PURPOSE: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (Ikr), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO). METHODS: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests. RESULTS: DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had Ikr blocking potential at clinically relevant concentrations. CONCLUSIONS: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.

  • 10.
    Bengtsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Engwall, Ann-Cathrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Jergil, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Differences in gene expression in the developing rat brain using cDNA microarray and real-time PCRManuscript (preprint) (Other academic)
    Abstract [en]

    The blood-brain barrier (BBB) is formed by endothelial cells, connected by tight junction proteins restricting paracellular transport. Transport of substances into the brain may also be limited due to active efflux transporters. Not much is known about the development of tight junction proteins and active transporters in the BBB, and how this affects drug distribution to the brain at different ages. The aim of this study was to analyze possible differences in expression of tight junction proteins and active transporters in the BBB at different postnatal ages in the rat. Brain capillary-rich fractions (BCRF) were collected and gene expression levels were compared at three postnatal ages using microarray analysis. BCRF was also analyzed for the mRNA expression levels of P-gp Abcb1 (P-gp), Abcg2 (Bcrp), Slc22a8 (Oat3) and occludin using real-time PCR at 12 different postnatal ages between postnatal Day 1 and Adult. In the array analysis, 28 genes of interest were found to be differentially expressed. The mRNA levels of Abcg2 decreased to one seventh from postnatal Day 1 to Day 15. The levels of Slc22a8 increased from birth and reached a plateau at Day 3 - 12 followed by a decrease to Day 15. These findings show that active transporters are differentially expressed in the developing BBB, possibly affecting drug distribution to the brain. No change in the mRNA levels for Abcb1 or occludin was observed.

  • 11.
    Broberg, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Tissue-specific regulation of CYP19A1 – Implications for toxicological screening methods and breast cancer treatment strategies2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Background: Aromatase, encoded by CYP19A1, is an enzyme that converts androgens to estrogens. The enzyme is expressed in various tissues in the human body. The aim of this study is to investigate if there is a tissue-specific effect of 1α,25-dihydroxyvitamin D3 by analyzing the gene expression of CYP19A1 in cell lines representing the human adrenal cortex, the human ovarian, human osteoblastic cells and human breast glands. The results could be important for the evaluation of the NCI-H295R cell line as a toxicological screening method in which aromatase is an important enzyme and in the development of endocrine cancer therapy with CYP19A1 as a target.Methods: The change in gene expression followed exposure for 1α,25-dihydroxyvitamin D3 was measured  using qRT-PCR. Primers were specific for the total aromatase gene or promoter-specific regions of the gene.Results: The results show that 1α,25-dihydroxyvitamin D3 exerts a tissue specific effect on CYP19A1 expression. The gene expression was increased in the ovarian cells, the osteoblastic cells and the adrenocarcinoma cells, while it was decreased in the breast cancer cells. The results also showed an altered gene expression due to a promoter-specific regulation.Conclusion: It has become more clear that 1α,25-dihydroxyvitamin D3 could be a potential anti-breast cancer agent in the future. However, the difference in aromatase gene expression between the breast cancer cells and the adrenocarcinoma NCI-H295R cells indicates that the NCI-H295R cell line might not be reliable for toxicological screening on sex hormone production on its own, unless there is a way to take into account the tissue-specific regulation of CYP19A1.

  • 12.
    Dahlin, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergman, Ulrika
    Jansson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Björk, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Transfer of dopamine in the olfactory pathway following nasal administration in mice2000In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 17, no 6, p. 737-742Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of the study was to investigate whether dopamine is transferred along the olfactory pathway to the brain following nasal administration to mice. METHODS: [3H]-Dopamine was administered nasally or intravenously to female mice. Brain tissue samples were excised and the radioactive content was measured. The precise localisation of dopamine radioactivity in the brain was studied using autoradiography. The presence of dopamine or its metabolites in the olfactory bulb and mucosa was ascertained using thin layer chromatography (TLC). RESULTS: After administration of [3H]-dopamine into the right nostril, the amount of dopamine in the right bulb increased with time until. after 4 h, it was 27 times higher than in the left bulb. Among the other brain tissue samples, significantly higher amount of radioactivity was detected in the lateral olfactory tract. Radioactivity in the right olfactory bulb was shown by autoradiography to be selectively located in the peripheral layers 1 to 4 h after administration. Selective uptake of radioactivity was not seen in other regions of the brain. TLC data indicated that approximately 75% and 10% of the radioactivity in the olfactory bulb and mucosa, respectively, coeluted with dopamine. CONCLUSIONS: The results indicate that unchanged dopamine is transferred into the olfactory bulb following nasal administration of [3H]-dopamine.

  • 13.
    Dencker, Lennart
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Oskarsson, Agneta
    Tegnell, Anders
    Liminga, Ulla Wändel
    Mängden kvicksilver i Pandemrix är inte förenad med ökad hälorisk2009In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 106, no 52, p. 3522-Article in journal (Refereed)
  • 14.
    Eskandari, Bahare
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    NSAID-läkemedel och deras passage över till modersmjölk2015Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Sammanfattning

    Bakgrund: Efter Sveriges inträde i EU har det skett förändringar i den godkännande proceduren av läkemedel. Generikaprepratens och originalläkemedlens FASS-texter kan skilja sig åt trots att det är samma substans och detta har uppmärksammats av patienterna. I detta arbete granskas läkemedelsgruppen NSAID och deras amningstexter i FASS i avseende på amning.

    Material och metod: Det tilldelades en Excel-fil av LIF som innehöll information om bland annat läkemedelsnamn, styrka och företag. Sedan jämfördes deras amningstext i FASS med klassificeringssystemets kriterier som står i FASS. Det kunde ske tre typer av korrigeringar som benämndes K, S och J. Dessa läkemedel granskades för att man skulle få en uppfattning om hur bra dessa hade blivit klassificerade utifrån klassificeringssystemets kriterier. Databasen pubmed användes för informationssökning.

    Diskussion: Den slutliga bedömningen av hur säkert ett läkemedel är kommer att bero på fyra faktorer, mängden läkemedel i bröstmjölken, biotillgängligheten hos barnet, läkemedlets toxicitet samt elimineringsförmågan hos barnet.Det kan finnas flera skäl till varför informationstexten i FASS inte stämmer överens med klassificeringen eller att det är olika klassificeringar för samma substans. Den främsta anledningen kan vara lagförändringen som skedde gällande godkännandeproceduren av läkemedel där generikapreparatens information kan skilja sig åt beroende på vilket land de valde som referensland till originalläkemedlet.

    Slutsats: I fall med barn inblandade och bristfälliga uppgifter brukar det generella rådet bli att antingen sluta amma eller ta uppehåll från läkemedelsbehandlingen för att undvika eventuella biverkningar man inte känner till än. Effekten på barnet blir istället baserad på andra vetenskap vi har om mekanismen bakom läkemedels passage till modersmjölk och molekylers egenskaper. Som lösning till felklassificeringarna i FASS föreslås referenshänvisnig, införa klassificeringssystemet i produktresumén och ett annat klassificeringssystem som aktivt granskas då det sker uppdateringar hela tiden.

  • 15.
    Fernández, Estíbaliz L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Tallkvist, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Expression of ZnT-1 (Slc30al) and MT-1 (Mt1) in the conceptus of cadmium treated mice2007In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 24, no 3-4, p. 353-358Article in journal (Refereed)
    Abstract [en]

    There are indications that Cd-induced malformations in rodents are related to a disrupted flux of Zn to the developing embryo. The aim of the present study was to detect ZnT-1 (Slc30al) and MT (Mt1) protein in structures within the decidua, yolk sac and embryo of mice and to determine whether Cd affects ZnT-1 or MT-1 gene expression in these tissues. ZnT-1 was detected in the placental labyrinth, in the ventral part around the floor plate, in the inner cell layers of the rhombencephalon and in the ventral area of the otic vesicle. MT protein was detected in the yolk sac and in the Surface ectoderm of some embryonic areas, such as the pharyngeal arches. ZnT-1 and MT-1 transcripts were most abundant in the decidua and yolk sac, whereas the abundance of these genes was relatively low in the embryo. Cd exposure down-regulated ZnT-1 and up-regulated MT-1 gene expression in all structures investigated, indicating that maternal Cd exposure may alter Zn homeostasis in the conceptus.

  • 16.
    Isaksson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    The Role of Glia Response in L-DOPA-induced Dyskinesia2013Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Pakinson’s disease (PD) is a neurodegenerative disease which primarily treatment is substitution therapy with L-dopa. However, the drug is associated with the development of L-dopa induced dyskinesias (LID), which is more severe in some individuals. In this study we investigated proteomic changes in the striatum of low and high dyskinetic animals compared to control using the 6-OHDA rat model of PD. AMT (Accurate Mass and Time) tag mass spectrometry was used in order to detect proteomic changes which were then validated with fluorescent immunohistochemistry (IHC). The results from experiments in normal tissue strongly indicate that the CRYAB (αB-crystallin) immunoreactive (IR) cells are of oligodendrocyte lineage but not fully matured oligodendrocytes. The experiments in lesioned tissue display an upregulation of CRYAB in the high dyskinetic and control group, while the low dyskinetic group displayed a significant normalization in the lesioned striatum. GFAP (Glial Fibrillary Acidic Protein) was upregulated in the lesioned side compared to intact in all animals, indicating an increased number of astrocytes in the lesioned animals, which could be a consequence of the degeneration of the dopaminergic neurons. Our results suggest that the CRYAB-IR cells are oligodendrocytes that mature upon injury and that low levels of CRYAB is associated with less severe dyskinesia. 

  • 17.
    Jergil, Måns
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Forsberg, Maud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salter, Hugh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Nau, Heinz
    Center for Food Science, Department of Food Toxicology, Veterinary University, Hannover.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Short-Time Gene Expression Response to Valproic Acid and Valproic Acid analogs in Mouse Embryonic Stem Cells2011In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 121, no 2, p. 328-342Article in journal (Refereed)
    Abstract [en]

    The prediction of potential developmental toxicity in vitro could be based ontoxicogenomic endpoints a short time after exposure in cultured embryo-derived celllines. Our previous microarray studies in P19 mouse embryonal carcinoma cells andmouse embryos have indicated that the teratogen valproic acid (VPA), an inducerof neural tube defects, deregulates the expression of a large number of genes, manyof which have critical roles in neural tube formation and closure. In this study weexposed undifferentiated R1 mouse embryonic stem (ES) cells to VPA and VPA analogto define genes whose expression responses may be related to teratogenic potential.After 6 h of exposure, RNA samples were subjected to microarray analysis usingCodeLinkTM Mouse Whole Genome Bioarrays. VPA (1 mM) and the teratogenic VPAanalog (S)-2-pentyl-4-pentynoic (0.25 mM or 0.5 mM) deregulate a large numberof genes, whereas for the non-teratogenic (and potentially pharmacologically active)analog 2-ethyl-4-methyl-pentanoic acid (1 mM) the expression of only a few geneswas affected. Biological process ontology groups related to embryonic development,morphogenesis, and cell behavior were overrepresented among the affected teratogentarget genes. Multivariate analysis indicated that as few as five genes (out of ~2500array probes correlating with the separation) could separate the data set accordingto teratogenicity. Genes deregulated by the two teratogens showed a substantialoverlap with genes previously found to be deregulated by VPA in P19 cells and mouseembryos. A panel of candidate genes was defined as potential markers predictiveof teratogenicity and evaluated through TaqMan low density array analysis. Theteratogens butyrate and trichostatin A, which like VPA and (S)-2-pentyl-4-pentynoicacid are known histone deacetylase (HDAC) inhibitors, induced similar responsesas these two teratogens for a large subset of markers. This indicates that HDACinhibition may be a major mechanism by which VPA induces gene deregulation andpossibly teratogenicity. Other teratogenic compounds tested had no effect on thepanel of selected markers, indicating that they may not be predicitive of teratogenicityfor compounds acting through other mechanisms than VPA.

  • 18.
    Jergil, Måns
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Strehl, Raimund
    Salter, Hugh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Hyllner, Johan
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Exploring Transcriptional Response toValproic Acid and Valproic Acid Analogs in Human Embryonic Stem CellsManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Developmental toxicity is a major concern for manufacturers of new pharmaceuticals,and current testing requires many laboratory animals. Human embryonic stem (hES)cells, potentially being close in function to cells in the developing embryo, mayprovide a technology for classification of candidate drugs in the early phase of toxicityevaluation. Altered gene expression in such system may be predictive of teratogenicproperties of a substance if important gene regulatory pathways are affected, and mayhence be used as appropriate endpoint. In the present study we used the pluripotenthES cell line SA002 (Cellartis AB), and microarrays to profile the response tovalproic acid (VPA), a known human teratogen causing increased risk of e.g. spinabifida and cognitive disorders in exposed embryos We also investigated three closelyrelated VPA analogs with differing in vivo teratogenicity in mice as well as histonedeacetylase (HDAC) inhibition, a proposed teratogenic mechanism of VPA. hEScells in an undifferentiated state were exposed for 24 h to either 1 mM VPA, 0.25mM or 0.5 mM (S)-2-pentyl-4-pentynoic acid a more potent teratogen and HDACinhibitor than VPA, 1 mM 3-propyl-heptanoic acid, a potent teratogen but not anHDAC inhibitor, 1 mM 2-ethyl-4-methyl-pentanoic acid, a non-teratogen and non-HDAC inhibitor, or 0.1% DMSO. Gene expression was subsequently profiled usingCodelink Human Whole Genome BioArrays. We found the HDAC inhibitors tostrongly deregulate largely the same genes. Further, a concordance of altered geneontology groups, predominantly neurogenic processes, was evident between all theteratogenic substances. Also, comparison with mouse ES cells showed an overlap ofderegulated genes as well as species specific gene to be deregulated.

  • 19.
    Johansson, K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Olsson, S
    Hellman, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Meyboom, RHB
    An analysis of Vigimed, a global E-mail system for the exchange of pharmacovigilance information2007In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 30, no 10, p. 883-889Article in journal (Refereed)
    Abstract [en]

    Background and aim: The Internet provides novel ways for communication and data exchange between national regulators. One innovation was the introduction of Vigimed, an e-mail discussion forum for national pharmacovigilance centres (NPCs). We reviewed a sample of Vigimed messages to learn more about this new tool and about the problems encountered in everyday pharmacovigilance and how these are handled. Methods: We analysed the contents of 100 subsequent questions and the corresponding responses as stored in the Vigimed datafile. Results: To the 100 questions circulated through Vigimed, 575 answers were received; mean number of answers per question 6, range 0-20. Fifty-five (77%) of the 71 collaborating countries and 88 (43%) of the 204 individuals who had access in the study period had submitted at least one question or answer. These countries were in all parts of the world and in various phases of development. A total of 38% of the questions concerned the regulatory status of a drug; 30% safety issues; 13 % regulatory actions under consideration; and 10% drug use-related problems (more than one category possible). Of the questions, 89% concerned established drugs; 11% were classified as new. A total of 90% of the questions concerned specific active substances or drug groups. Of the drugs, 73% were classified as 'orthodox' and 9% as herbal; 4% were vaccines and 4% excipients. Emerging drug groups (anatomical therapeutic chemical codes) were NSAIDs and analgesics (M01, N02), antibacterials (J01), antiobesity drugs (A08), psychotropic drugs (N05) and antihistamines (R06). Discussion: NPCs operate in a restricted environment and there is little published information about the daily practices and experiences at NPCs. Our study concerned a sample in a limited period in time. In the meantime, the use of Vigimed has greatly expanded. The data in the Vigimed records are subjected to confidentiality in regard to the identities of countries, staff members, drug products and pharmaceutical companies, which tin-tits the presentation of data in a publication. For information about the actions taken to manage the matters and problems raised in Vigimed it would have been necessary to contact the NPCs and acquire follow-up data. Conclusions: The Vigimed e-mail discussion group was rapidly incorporated into the routines at NPCs in many countries around the world. When two or more persons per country have access, participation increases. The matters raised predominantly refer to regulatory policy, safety concerns and drug use-related problems, and mainly concern established drugs. The latter emphasises the need for persistent monitoring of all drugs. New safety concerns are often sensitive and uncertain; the timely and efficient communication of such suspicions benefits from an environment of confidentiality. The Vigimed records give a unique view of real-life pharmacovigilance, of the matters addressed, the problems encountered, the data needed and the ways in which NPCs help each other. Such information can help make pharmacovigilance more efficient and effective.

  • 20.
    Karlsson, Emelie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    The role of αB-crystallin in levodopa induced dyskinesia2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    αB-crystallin (CRYAB), a small heat shock protein (sHSP) possibly of oligodendrocytic origin, is found to be up-regulated in brain tissues of untreated parkinsonian rats and in highly dyskinetic rats after treatment with levodopa (L-DOPA), whereas the levels are significantly lower in low dyskinetic animals. The aim of the project was to find out more about CRYAB´s role in untreated and highly dyskinetic animals. By using fluorescent immunohistochemistry (IHC) CRYAB was investigated to find out in what stage of the oligodendrocytic lineage the sHSP is expressed, also a cell culture method for CRYAB expression has been investigated. The results from experiments in healthy brain tissue, showed partly double positive cells for late premyelinating and myelinating oligodendrocyte markers CRYAB+/MAG+ and CRYAB+/RIP+. A method for creating CRYAB expressing cell culture with myelinating oligodendrocytes was examined and resulted in partly double positive cells for CRYAB+/MBP+ cells after addition of extra oligodendrocytes. The results indicate that CRYAB is expressed somewhere in between premyelinating and myelinating steps in the oligodendrocytic lineage. Also an oligodendrocytic cell culture expressing CRYAB have been developed for further investigations of CRYAB and its properties, but is in need of optimization for a better stability and standardization.

  • 21.
    Kultima, Kim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Fernández, Estíbaliz L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Gustafson, Anne-Lee
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Cadmium-induced gene expression changes in the mouse embryo, and the influence of pretreatment with zinc2006In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 22, no 4, p. 636-646Article in journal (Refereed)
    Abstract [en]

    Cadmium (Cd) administered to female C57BL/6 mice on gestation day 8 induces a high incidence of anterior neural tube defects (exencephaly). This adverse effect can be attenuated by maternal pretreatment with zinc (Zn). In this study we used replicated microarray analysis and real-time PCR to investigate gene expression changes induced in the embryo 5 and 10h after maternal Cd exposure in the absence or presence of Zn pretreatment. We report nine genes with a transcriptional response induced by Cd, none of which was influenced by Zn pretreatment, and two genes induced only by combined matemal Cd exposure and Zn pretreatment. We discuss the results in relation to the possibility that Cd is largely excluded from the embryo, that the teratogenic effects of Cd may be secondary to toxicity in extraembryonic tissues, and that the primary protective role of Zn may not be to reverse Cd-induced transcription in the embryo.

  • 22.
    Kultima, Kim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Jergil, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Gustafsson, Anne-Lee
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Early transcriptional responses in mouse embryos as a basis for selection of molecular markers predictive of valproic acid teratogenicityManuscript (preprint) (Refereed)
    Abstract [en]

    Cell-based in vitro assays would potentially reduce animal testing in preclinical drugdevelopment. Mouse embryos exposed to the teratogenic drug valproic acid (VPA)in utero for 1.5, 3 or 6 h on gestational day 8 were analyzed using microarrays.Significant effects on gene expression were observed as early as 1.5 h, and 85 probeswere deregulated across all time points. To find transcriptional markers of VPAinduceddevelopmental toxicity, the in vivo data were compared to previous in vitrodata on embryonal carcinoma P19 cells exposed to VPA for 1.5, 6 or 24 h. Maximalconcordance between embryos and cells was at the 6-h time points, with 163 genesshowing similar deregulation. Developmentally important Gene Ontology terms, suchas “morphogenesis” and “tube development” were overrepresented among putativeVPA target genes. The genes Gja1, Hap1, Sall2, H1f0, Cyp26a1, Fgf15, Otx2, andLin7b emerged as candidate in vitro markers of potential VPA-induced teratogenicity.

  • 23.
    Kultima, Kim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Nyström, Anna-Maja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Gustafson, Anne-Lee
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Valproic acid teratogenicity: a toxicogenomics approach2004In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 112, no 12, p. 1225-1235Article in journal (Refereed)
    Abstract [en]

    Embryonic development is a highly coordinated set of processes that depend on hierarchies of signaling and gene regulatory networks, and the disruption of such networks may underlie many cases of chemically induced birth defects. The antiepileptic drug valproic acid (VPA) is a potent inducer of neural tube defects (NTDs) in human and mouse embryos. As with many other developmental toxicants however, the mechanism of VPA teratogenicity is unknown. Using microarray analysis, we compared the global gene expression responses to VPA in mouse embryos during the critical stages of teratogen action in vivo with those in cultured P19 embryocarcinoma cells in vitro. Among the identified VPA-responsive genes, some have been associated previously with NTDs or VPA effects [vinculin, metallothioneins 1 and 2 (Mt1, Mt2), keratin 1-18 (Krt1-18)], whereas others provide novel putative VPA targets, some of which are associated with processes relevant to neural tube formation and closure [transgelin 2 (Tagln2), thyroid hormone receptor interacting protein 6, galectin-1 (Lgals1), inhibitor of DNA binding 1 (Idb1), fatty acid synthase (Fasn), annexins A5 and A11 (Anxa5, Anxa11)], or with VPA effects or known molecular actions of VPA (Lgals1, Mt1, Mt2, Id1, Fasn, Anxa5, Anxa11, Krt1-18). A subset of genes with a transcriptional response to VPA that is similar in embryos and the cell model can be evaluated as potential biomarkers for VPA-induced teratogenicity that could be exploited directly in P19 cell-based in vitro assays. As several of the identified genes may be activated or repressed through a pathway of histone deacetylase (HDAC) inhibition and specificity protein 1 activation, our data support a role of HDAC as an important molecular target of VPA action in vivo.

  • 24.
    López Fernández de Villaverde, Estíbaliz
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Mechanisms behind Cadmium-Induced Teratogenicity2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Heavy metals polluting our environment cause concern for developing organisms. Among them, cadmium with extremely slow elimination from the body, causes lower birth weight in humans but has not been classify as a human teratogen. Studies in different laboratory animals have shown that cadmium indeed is a potent teratogen. Exposure to cadmium during early mouse embryonic stages (e.g. day 7-8 post-coitus) interferes with the closure of the anterior neural pore producing exencephalic embryos. The underlying mechanisms are not understood, but the heavy accumulation of cadmium in extra- and intraembryonic endoderm and chorioallantoic placenta, however not in the neuroepithelium, suggests that the effects on neural tube closure is due to indirect mechanisms. In this thesis, the disruption in the mouse embryo at the time of neural tube closure of the hierarchies of some signalling pathways and gene regulatory networks that control embryonic development has been studied after cadmium exposure. Cadmium was shown to cause DNA damage as measured by Comet assay, and to activate genes and proteins in the apoptotic pathways (p53, p21, Bcl-2, Bax, and caspase-3), increasing the number of apoptotic cells mostly in areas of physiological cell death, especially in the neuroepithelium. Many of these effects could be reversed by zinc pre-treatment, known to counteract the teratogenic effect of cadmium. Cadmium was also shown to affect Zn-transport and –regulatory proteins in the embryo, but perhaps more importantly in yolk sac placenta, and in the decidua (ZnT-1, MT-I, and ZIP-4). Using gene arrays, cadmium was found to considerably affect gene expression of rather few genes, such as those of metallothioneins and stress-related proteins, supporting in principle an extraembryonic site of action of cadmium. In addition, a number of genes expressed in the anterior visceral endoderm (Hesx1, HNF3β, Cerl, Otx2 and Sox2) where cadmium accumulates, and known to signal to the anterior neuroepithelium, was affected by cadmium. This finding may suggest a new principle for chemical teratogenesis.

    List of papers
    1. I.Disturbing endoderm signalling to anterior neural plate of vertebrates by the teratogen cadmium.
    Open this publication in new window or tab >>I.Disturbing endoderm signalling to anterior neural plate of vertebrates by the teratogen cadmium.
    2004 In: Reproductive Toxicology, Vol. 18, p. 653-660Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93848 (URN)
    Available from: 2005-11-28 Created: 2005-11-28Bibliographically approved
    2. Cadmium-induced changes in apoptotic gene expression levels and DNA damage in mouse embryos are blocked by zinc.
    Open this publication in new window or tab >>Cadmium-induced changes in apoptotic gene expression levels and DNA damage in mouse embryos are blocked by zinc.
    Show others...
    2003 In: Toxicological Sciences, Vol. 76, p. 162-170Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93849 (URN)
    Available from: 2005-11-28 Created: 2005-11-28Bibliographically approved
    3. Expression of ZnT-1 (Slc30al) and MT-1 (Mt1) in the conceptus of cadmium treated mice
    Open this publication in new window or tab >>Expression of ZnT-1 (Slc30al) and MT-1 (Mt1) in the conceptus of cadmium treated mice
    2007 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 24, no 3-4, p. 353-358Article in journal (Refereed) Published
    Abstract [en]

    There are indications that Cd-induced malformations in rodents are related to a disrupted flux of Zn to the developing embryo. The aim of the present study was to detect ZnT-1 (Slc30al) and MT (Mt1) protein in structures within the decidua, yolk sac and embryo of mice and to determine whether Cd affects ZnT-1 or MT-1 gene expression in these tissues. ZnT-1 was detected in the placental labyrinth, in the ventral part around the floor plate, in the inner cell layers of the rhombencephalon and in the ventral area of the otic vesicle. MT protein was detected in the yolk sac and in the Surface ectoderm of some embryonic areas, such as the pharyngeal arches. ZnT-1 and MT-1 transcripts were most abundant in the decidua and yolk sac, whereas the abundance of these genes was relatively low in the embryo. Cd exposure down-regulated ZnT-1 and up-regulated MT-1 gene expression in all structures investigated, indicating that maternal Cd exposure may alter Zn homeostasis in the conceptus.

    Keywords
    cadmium, zinc, embryo, malformation, ZnT-1 (Slc30al), metallothionein (Mt1)
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-93850 (URN)10.1016/j.reprotox.2007.06.006 (DOI)000251463300012 ()17669619 (PubMedID)
    Available from: 2005-11-28 Created: 2005-11-28 Last updated: 2018-01-13Bibliographically approved
    4. Cadmium-induced gene expression changes in the mouse embryo, and the influence of pretreatment with zinc
    Open this publication in new window or tab >>Cadmium-induced gene expression changes in the mouse embryo, and the influence of pretreatment with zinc
    Show others...
    2006 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 22, no 4, p. 636-646Article in journal (Refereed) Published
    Abstract [en]

    Cadmium (Cd) administered to female C57BL/6 mice on gestation day 8 induces a high incidence of anterior neural tube defects (exencephaly). This adverse effect can be attenuated by maternal pretreatment with zinc (Zn). In this study we used replicated microarray analysis and real-time PCR to investigate gene expression changes induced in the embryo 5 and 10h after maternal Cd exposure in the absence or presence of Zn pretreatment. We report nine genes with a transcriptional response induced by Cd, none of which was influenced by Zn pretreatment, and two genes induced only by combined matemal Cd exposure and Zn pretreatment. We discuss the results in relation to the possibility that Cd is largely excluded from the embryo, that the teratogenic effects of Cd may be secondary to toxicity in extraembryonic tissues, and that the primary protective role of Zn may not be to reverse Cd-induced transcription in the embryo.

    Keywords
    cadmium, exencephaly, microarray, mouse embryo, neural tube defects, toxicogenomics, zinc
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-93851 (URN)10.1016/j.reprotox.2006.05.007 (DOI)000241622800014 ()16842966 (PubMedID)
    Available from: 2005-11-28 Created: 2005-11-28 Last updated: 2018-01-13Bibliographically approved
  • 25.
    Mahteme, Haile
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Biochemistry.
    Khamis, Harry
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Information Science.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Uptake of 5-fluorouracil (5-FU) in peritoneal metastases in relation to the route of drug administration and tumour debulking surgery: an autoradiographic study in the rat2004In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 40, no 1, p. 142-147Article in journal (Refereed)
    Abstract [en]

    Patients with peritoneal metastases from colorectal cancer have a poor prognosis. Aggressive treatment by debulking surgery and intraperitoneal (i.p.) chemotherapy has been suggested as an alternative therapy. However, the drug penetrance into the tumour in relation to the administration route and surgical reduction of the tumour is not well known. We compared locoregional administration with intravenous (i.v.) injection. Thirty-four in-bred rats with peritoneal metastases were randomly allocated into eight groups and injected with 14C-labelled 5-fluorouracil (5-FU) either through the i.v. or i.p. route, with or without a preceding tumour debulking, and were sacrificed after 2 or 8 h. Tumour radioactivity was visualised by autoradiography and quantified by a computer-based image analysis. After 8 h, 19 debulked and i.p.-injected tumours had a higher drug uptake, 63.2+/-28 (mean+/-standard deviation (SD)) kBq/g than 62 native i.p.-injected tumours (32.8+/-14) or 22 debulked and i.v.-injected tumours (18.5+/-18, P=0.002). After 8 h, 9 small tumours (<median 571 pixels) which underwent i.p. injection and tumour reduction had a higher drug uptake (77.4+/-26) than 29 non-debulked and i.p.-injected (35.1+/-17) or eight debulked and i.v. injected tumours (23.0+/-16, P=0.004). For larger tumours (>/=median 571 pixels), 16 debulked and i.p.-injected tumours had a higher radioactivity (drug uptake) (150.7+/-63) at 2 h than 49 i.p.-injected native tumours (48.5+/-59) or 11 reduced and i.v.-injected tumours (19.9+/-13, P=0.03). At 8 h, 10 debulked and i.p.-injected tumours had a higher drug uptake (50.3+/-24) than 33 native and i.p.-injected (30.8+/-10) or 14 debulked and i.v.-injected tumours (16.0+/-19, P=0.001). These results indicate that a debulking procedure and locoregional treatment of peritoneal metastases is associated with an increased level of 5-FU in the tumours.

  • 26.
    Salas Cucarull, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Comparison of feeder cells formed from primary or SV40 immortalised mouse embryonic fibroblasts for embryonic stem cell culture2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The embryonic stem cell test (EST) is a method first validated by ECVAM in 2003 that uses embryonic stem cells (ESCs) to study embryotoxicity of different compounds classifying them as embryotoxic, weakly embryotoxic and non-embryotoxic by looking at some endpoints as inhibition of formation of beating cardiomyocytes, cytotoxicity in ESCs and cytotoxicity in mouse 3T3 fibroblasts after ten days culture. Usually ESCs are cultured on a feeder layer formed by inactivated primary mouse embryonic fibroblasts (MEFs), which are cells derived from the embryo. To reduce the number of animals sacrificed the present study has been investigating an improvement to the EST that consist in trying to grow ESCs above a feeder layer formed by inactivated primary MEFs infected by SV40 virus, being transformed into immortalized feeders. To compare both types of feeder cells some endpoints such as morphological comparison between them, the time they take to form a confluent feeder layer, expression of stemness markers Nanog, Pou5f, and Sox2 by ESCs cultured on both feeder layers or formation of embryoid bodies formed from these ESCs were analysed. Results were promising in the first stages, as no morphological differences were observed but finally data seem to point that SV40 feeders cannot form a feeder layer as efficient as the one formed by regular feeders. However, this cannot be affirmed, as contamination occurred repeatedly during study and results obtained were not as good as it would have been desirable.

  • 27.
    Scholz, Birger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Mattsson, Anna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Axelsson, Jeanette
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Halldin, Krister
    Stigson, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Sex-dependent gene expression in early brain development of chicken embryos2006In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 7, p. 12-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Differentiation of the brain during development leads to sexually dimorphic adult reproductive behavior and other neural sex dimorphisms. Genetic mechanisms independent of steroid hormones produced by the gonads have recently been suggested to partly explain these dimorphisms.

    RESULTS:

    Using cDNA microarrays and real-time PCR we found gene expression differences between the male and female embryonic brain (or whole head) that may be independent of morphological differentiation of the gonads. Genes located on the sex chromosomes (ZZ in males and ZW in females) were common among the differentially expressed genes, several of which (WPKCI-8, HINT, MHM non-coding RNA) have previously been implicated in avian sex determination. A majority of the identified genes were more highly expressed in males. Three of these genes (CDK7, CCNH and BTF2-P44) encode subunits of the transcription factor IIH complex, indicating a role for this complex in neuronal differentiation.

    CONCLUSION:

    In conclusion, this study provides novel insights into sexually dimorphic gene expression in the embryonic chicken brain and its possible involvement in sex differentiation of the nervous system in birds.

  • 28.
    Shiikh Dahir, Mahamed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Effects of treatments with angiogenesis inhibitors on tumor stroma in animal experimental models of child cancer Neuroblastoma2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Neuroblastoma, a neuroendocrine tumor, is the most common cancer in infancy. 75 % of those affected are under the age of 5. The disease is heterogeneous and survival rate is low.

     

    Current treatment of neuroblastoma consists of surgery, radiation and chemotherapy, where the targets for the treatment are the malign cells. Due to the cancer cells instable genome there is a risk for resistance development. This negatively impacts the treatments goal of hindering tumor growth and spread.  Tumor growth is not only determined by malign cells but also the interactions of those tumor cells with tumor vessels and different types of cells in the tumor stroma.

     

    The aim of this paper is to develop a relevant histological method to study the properties of tumor stroma in tumor sections retrieved from human NB tumor xenografts in mice treated with angiogenesis inhibitors SU11657 and Zoledronic acid. The study is a continuation of previous studies with the inhibitors which have shown good effect on tumor growth and angiogenesis on neuroblastoma.

     

    In the short term treatment with SU11657 and Zoledron acid showed that tumor growth declined. In the longer treatment with SU11657 the growth didn’t decline with the same rate compared to the short term treatment. Angiogenesis on the other hand decreased in all the treatments independent of treatment duration. The histological staining with Sirius red revealed that treated tumors had an increased amount of stroma compared to the untreated tumors.

     

    In conclusion the relative increase of tumor volume, decreased number of vessels and expansion of tumor stroma in the longer treatment with SU11657 indicated that tumors might survive the angiogenesis inhibitor treatment through expansion/activation of its stroma. The histological staining with Sirius red in saturated picric acid marked the collagen, i.e. stroma, well and enabled quantification of the stroma.

  • 29.
    Stigson, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Jergil, Måns
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Scholz, Birger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Alm, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Gustafson, Anne-Lee
    Dencker, Lennart
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Molecular targets and early response biomarkers for the prediction of developmental toxicity in vitro2007In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 35, no 3, p. 335-342Article in journal (Refereed)
    Abstract [en]

    There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers - even a single one - could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool in defining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a potentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.

  • 30.
    Svensson, Camilla
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Adseverin – An Immune-Specific Target of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces thymus atrophy and immunosuppression in all animal species examined and these effects constitute a potential risk to humans. TCDD can via binding to the intracellular aryl hydrocarbon receptor (AhR), modulate transcription of a number of genes and the aim of this thesis has been to identify such genes, which may explain the mechanisms behind TCDD-mediated immunotoxicity.

    The differential display polymerase chain reaction (PCR) technique was applied to screen for TCDD-responsive genes in the thymus of C57BL/6 mice. The major finding was that TCDD up-regulates the level of adseverin, an actin-severing protein. The induction of adseverin by TCDD was dose-dependent and could be detected before any signs of thymus atrophy were apparent. Reverse transcription-PCR analysis of the levels of adseverin in different tissues revealed that the up-regulation was restricted to lymphoid tissues with hematopoietic activity. Adseverin was not induced in lymph nodes indicating that peripheral resting T cells are refractory to TCDD exposure.

    Within the thymus, the induction of adseverin was shown to be a direct AhR-mediated effect on thymocytes, which are known target cells of TCDD. In contrast, no adseverin induction was observed in thymic stroma although TCDD clearly reached these cells, as they up regulated CYP1A1, a marker for TCDD exposure. By sorting the different maturation stages of thymocytes it was demonstrated that adseverin under normal conditions is expressed at high levels during early differentiation stages and then gradually down regulated as the thymocytes differentiate. Interestingly, TCDD exposure counteracted the down regulation of adseverin by inducing adseverin at all stages of thymocyte differentiation. This may explain previous observations that TCDD affects many different stages of thymocyte maturation.

    It is suggested that overexpression of adseverin leads to increased depolymerisation of the actin cytoskeleton. This may be detrimental for normal thymocyte/T cell activities such as migration and activation that are dependent on strictly controlled actin reorganisation. Thus, adseverin may be a critical target for TCDD and be involved in TCDD-induced immunotoxicity.

  • 31.
    Yilmaz, Ezgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    KARBAMAZEPIN-INDUCERAD LEVERTOXICITET - ETT LITTERATURARBETE2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Läkemedelsbiverkningar delas in i två grupper; typ A och typ B. Typ A-biverkningar är dosberoende medan typ B-biverkningar är idiosynkrasiska och beroende av immunsystemet. Levern är kroppens huvudsakliga metabola organ, och drabbas ofta av läkemedelinducerad toxicitet. Ibland inducerar läkemedelsmetaboliter levertoxicitet, vilket kan medieras av immunsystemet. Karbamazepin är ett antiepileptikum och orsakar levertoxicitet, men den exakta mekanismen är inte klarlagd. Syfte: Syftet med detta arbete är att undersöka om karbamazepins levertoxicitet är beroende av metabolismen av karbamazepin och/eller immunsystemet. Material och metoder: En strukturerad litteraturundersökning utfördes med hjälp av databasen PubMed. 7 artiklar inkluderades i sammanställningen. Resultat: Resultat från in vivo-studier identifierade metaboliter producerade av cytokrom P450-monooxygenaser (CYP450) hos de individer som utvecklade levertoxicitet inducerad av karbamazepin. Samtidigt noterades en ökad nivå CYP3A. Expressionen av en rad immunsystemsmarkörer ökade också vid karbamazepin-inducerad levertoxicitet, exempelvis TNF-α, som leder till apoptos. Slutsats: Utifrån inkluderade studier kan slutsatsen dras att karbamazepins levertoxicitet induceras av dess metaboliter via immunsystemet. Undersökningarna var huvudsakligen associationsstudier, vilket försvårar slutsatser kring kausalitet. Därför behöver ytterligare studier göras så att mekanismen helt kan klargöras.

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