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  • 1. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Bergman, Åke
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi. Swedish Toxicology Sciences Research Center (Swetox), Sweden.
    Andersson, Patrik L.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, s. 164-173Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 2. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Bergman, Åke
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, s. 164-173Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 3. Ali, Imran
    et al.
    Damdimopoulou, Pauliina
    Stenius, Ulla
    Halldin, Krister
    Cadmium at nanomolar concentrations activates Raf-MEK-ERK1/2 MAPKs signaling via EGFR in human cancer cell lines.2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 231Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cadmium (Cd) is an environmental contaminant classified as carcinogenic to humans by the International Agency for Research on Cancer, supported by data from occupational exposure. Environmentally relevant dietary exposure to Cd has recently been associated with osteoporosis and cancers of the prostate, endometrium, and breast in the general population. The low exposure effects have been proposed to result from endocrine modulative properties of Cd, which mimic the physiological actions of estrogen and androgen. However, the mechanism of action of Cd is an unanswered question. We have shown previously, using mouse models, that canonical estrogen receptor signaling is not involved in estrogen mimicry effects of Cd. Instead, low-level Cd exposure stimulated the mitogen-activated protein kinases (MAPKs) ERK1/2 in these mice. Here we investigate further the ERK1/2 MAPK signaling activation by Cd in vitro by using nanomolar concentrations of cadmium chloride (CdCl2) in three different human carcinoma cell lines: HepG2, MCF-7, and ECC-1. The findings also were confirmed in previously collected mouse tissue samples. We show that 10(-8)M levels of CdCl2 activate ERK1/2 (Tyr 204) and the p53 specific ubiquitin ligase Mdm2 (Ser 166) via Raf and MEK by acting through the epidermal growth factor receptor (EGFR). Furthermore, our results suggest that the CdCl2-induced activation of ERK1/2 and Mdm2 may interfere with the p53 response to genotoxic compounds in cancer cell lines. Our data collectively suggest that nanomolar levels of CdCl2 activate Raf-MEK-ERK1/2 via EGFR. We hypothesize that this signaling cascade may be involved in observed low exposure effects of Cd in certain human populations.

  • 4. Aspenström-Fagerlund, Bitte
    et al.
    Sundström, Birgitta
    Tallkvist, Jonas
    Ilbäck, Nils-Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Infektionssjukdomar.
    Glynn, Anders W.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Fatty acids increase paracellular absorption of aluminium across Caco-2 cell monolayers2009Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 181, nr 2, s. 272-278Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Passive paracellular absorption, regulated by tight junctions (TJs), is the main route for absorption of poorly absorbed hydrophilic substances. Surface active substances, such as fatty acids, may enhance absorption of these substances by affecting the integrity of TJ and increasing the permeability. It has been suggested that aluminium (Al) absorption occurs mainly by the paracellular route. Herein, we investigated if physiologically relevant exposures of fully differentiated Caco-2 cell monolayers to oleic acid and docosahexaenoic acid (DHA), which are fatty acids common in food, increase absorption of Al and the paracellular marker mannitol. In an Al toxicity test, mannitol and Al absorption through Caco-2 cell monolayers were similarly modulated by Al concentrations between 1 and 30mM, suggesting that absorption of the two compounds occurred via the same pathways. Exposure of Caco-2 cell monolayers to non-toxic concentrations of Al (2mM) and (14)C-mannitol in fatty acid emulsions (15 and 30mM oleic acid, 5 and 10mM DHA) caused a decreased transepithelial electrical resistance (TEER). Concomitantly, fractional absorption of Al and mannitol, expressed as percentage of apical Al and mannitol retrieved at the basolateral side, increased with increasing dose of fatty acids. Transmission electron microscopy was applied to assess the effect of oleic acid on the morphology of TJ. It was shown that oleic acid caused a less structured morphology of TJ in Caco-2 cell monolayers. Taken together our findings indicate that fatty acids common in food increase the paracellular intestinal absorption of Al. These findings may influence future risk assessment of human Al exposure.

  • 5.
    Cederlund, Ella
    et al.
    Karolinska Institute.
    Hedlund, Joel
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Hjelmqvist, Lars
    Karolinska Institute.
    Jonsson, Andreas
    Karolinska Institute.
    Shafqat, Jawed
    Karolinska Institute.
    Norin, Annika
    Karolinska Institute.
    Keung, Wing-Ming
    Harvard University.
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Jornvall, Hans
    Karolinska Institute.
    Characterization of new medium-chain alcohol dehydrogenases adds resolution to duplications of the class I/III and the sub-class I genes2011Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 191, nr 03-janArtikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Four additional variants of alcohol and aldehyde dehydrogenases have been purified and functionally characterized, and their primary structures have been determined. The results allow conclusions about the structural and evolutionary relationships within the large family of MDR alcohol dehydrogenases from characterizations of the pigeon (Columba livia) and dogfish (Scyliorhinus canicula) major liver alcohol dehydrogenases. The pigeon enzyme turns out to be of class I type and the dogfish enzyme of class III type. This result gives a third type of evidence, based on purifications and enzyme characterization in lower vertebrates, that the classical liver alcohol dehydrogenase originated by a gene duplication early in the evolution of vertebrates. It is discernable as the major liver form at about the level in-between cartilaginous and osseous fish. The results also show early divergence within the avian orders. Structures were determined by Edman degradations, making it appropriate to acknowledge the methodological contributions of Pehr Edman during the 65 years since his thesis at Karolinska Institutet, where also the present analyses were performed.

  • 6. Endo, Satoshi
    et al.
    Takada, Sayaka
    Honda, Ryo P.
    Müller, Kathrin
    Weishaupt, Jochen H.
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Ludolph, Albert C.
    Kamatari, Yuji O.
    Matsunaga, Toshiyuki
    Kuwata, Kazuo
    El-Kabbani, Ossama
    Ikari, Akira
    Instability of C154Y variant of aldo-keto reductase 1C32017Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 276, s. 194-202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aldo-keto reductase (AKR) 1C3 is a cytosolic enzyme that metabolizes steroids, prostaglandins, toxic aldehydes and drugs. Recently, some nonsynonymous single nucleotide polymorphisms of AKR1C3 have been suggested to impact steroid and drug metabolism. In this study, we examined the effects of C154Y and L159V variants of AKR1C3 on stability and function of the enzyme. Both variants had been detected in patients with the neurodegenerative disease amyotrophic lateral sclerosis. Recombinant wild-type (WT), C154Y and L159V enzymes were similar in specific activity, but C154Y displayed much lower thermostability than WT and L159V. C154Y was inactivated by 10-min incubation at >25 °C, and about 90% of its activity was lost at 40 °C. Differential scanning fluorimetry revealed that Tm (thermal denaturation midpoint) of C154Y was lower than that of WT. In order to study the cause of thermosensitivity of C154Y, we prepared C154F and C154S mutant AKR1C3s. Like C154Y, C154F was highly sensitive to thermal inactivation, whereas C154S showed almost the same thermostability as WT. The C154F and C154Y variants induced secondary and tertiary structural changes in AKR1C3 at 40 °C as reflected by their altered circular dichroism and 8-anilinonaphthalene-1-sulfonate fluorescence characteristics. These results suggest that the replacement of C154 with a residue possessing a bulky aromatic side-chain impairs the folding of the α-helix containing C154 and its neighboring secondary structures, leading to low thermostability of AKR1C3. AKR1C3 metabolizes cytotoxic 4-oxo-2-nonenal into a less toxic metabolite, and overexpression of WT in HEK293 cells alleviated the 4-oxo-2-nonenal-induced cytotoxicity. In contrast, the overexpression of C154Y in the cells did not show such a significant protective effect, suggesting that C154Y is unstable in cells.

  • 7.
    Forsby, A
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Walum, E
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Sterner, O
    The effect of six sesquiterpenoid unsaturated dialdehydes on cell membrane permeability in human neuroblastoma SH-SY5Y cells.1992Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 84, nr 1, s. 85-95Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effect of six sesquiterpenes containing an unsaturated dialdehyde functionality, on cell membrane permeability in the human neuroblastoma cell line SH-SY5Y has been studied. The kinetics of the membrane leakage after addition of the sesquiterpenes were determined by measuring the efflux of radioactivity from cells preloaded with tritiated 2-deoxyglucose. The concentrations that gave 5% and 20% efflux of radioactivity as compared with control cells (EC5 and EC20) were determined for each compound. In spite of the structural similarities between the compounds, the effects on cell membrane permeability varied considerably. EC20 for polygodial, which is the most active compound, is 2.5 microM after 20-min incubation, but no leakage could be determined for merulidial even at concentrations as high as 4 mM. Rather, this compound seems to stabilize or fix the cell membrane and a lower efflux of radioactivity was observed as compared to the control cells. A quantitative structure-activity relationship analysis for the five active compounds showed a good correlation between the membrane leakage activity and certain chemical characteristics. Structural features strongly correlated with high activity were found to be: The geometry and the atomic charges of the unsaturated dialdehyde functionality, the dipole moment, the energy difference between the lowest unoccupied molecular orbital and the highest occupied molecular orbital and the lipophilicity.

  • 8.
    Jornvall, H.
    et al.
    Jörnvall, H., Dept. of Med. Biochem./Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    Nordling, E.
    Persson, Bengt
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Multiplicity of eukaryotic ADH and other MDR forms2003Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 143-144, s. 255-261Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Eukaryotic genomes code for at least eight medium-chain dehydrogenases/reductases (MDR) enzyme families of two types, with and without Zn2+ at the active site. Four families have Zn2+: 'Dimeric alcohol dehydrogenases (ADHs)' (including liver ADHs), 'Tetrameric ADHs' (including the yeast ADHs), 'Cinnamyl ADHs' and 'Polyol DHs'. In the human genome, there are minimally 23 MDR genes, but the list is still growing from further interpretations. Of these, seven genes on chromosome 4 (and three pseudogenes) represent the ADH classes in the gene order IV, I?, Iß, Ia, V, II and III. The lineages leading to human ADH establish five levels of divergence, with nodes at the MDR/short-chain dehydrogenases/reductases (SDR), dimer/tetramer, class III/non-III, further class, and intraclass levels of divergence. These multiplicities allow conclusions on pathways of function for ADHs and suggest this activity to have two roles in addition to its function in metabolism, one of a basic defence nature, the other of regulatory value in higher eukaryotes. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

  • 9.
    Jornvall, Hans
    et al.
    Karolinska Institute, Sweden .
    Hedlund, Joel
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Bergman, Tomas
    Karolinska Institute, Sweden .
    Kallberg, Yvonne
    Karolinska Institute, Sweden .
    Cederlund, Ella
    Karolinska Institute, Sweden .
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Origin and evolution of medium chain alcohol dehydrogenases2013Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 202, nr 1-3, s. 91-96Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Different lines of alcohol dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication similar to 550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, "Cambrian explosion". Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins.

  • 10.
    Jönsson, Maria E.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Franks, Diana G.
    Woodin, Bruce R.
    Jenny, Matthew J.
    Garrick, Rita A.
    Behrendt, Lars
    Hahn, Mark E.
    Stegeman, John J.
    The tryptophan photoproduct 6-formylindolo 3,2-b carbazole (FICZ) binds multiple AHRs and induces multiple CYP1 genes via AHR2 in zebrafish2009Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 181, nr 3, s. 447-454Artikkel i tidsskrift (Fagfellevurdert)
  • 11.
    Jönsson, Maria E
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Franks, Diana G
    Woodin, Bruce R
    Jenny, Matthew J
    Garrick, Rita A
    Behrendt, Lars
    Hahn, Mark E
    Stegeman, John J
    The tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) binds multiple AHRs and induces multiple CYP1 genes via AHR2 in zebrafish2009Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 181, nr 3, s. 447-454Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tryptophan photooxidation product 6-formylindolo[3,2-b]carbazole (FICZ) has been proposed as a physiological ligand for the mammalian aryl hydrocarbon receptor (AHR), which it binds with high-affinity, inducing expression of cytochrome P450 1A1 (CYP1A1). We investigated whether the response to FICZ is evolutionarily conserved in vertebrates by measuring FICZ binding to two zebrafish AHRs (AHR1B and AHR2) and its ability to induce zebrafish CYP1 genes (CYP1A, CYP1B1, CYP1C1, CYP1C2, and CYP1D1) in vivo. Exposure of zebrafish embryos (48h-post-fertilization; hpf) to 10nM FICZ for 6h caused strong induction of CYP1A mRNA and a statistically significant but modest induction of CYP1B1 and CYP1C1. Neither CYP1C2 nor CYP1D1 expression was induced by FICZ under the conditions of dose, time or developmental stage examined here. CYP1A induction was significantly greater after 6h than after 12h of exposure to FICZ, suggesting a rapid degradation of inducer. The 6-h EC(50) values for induction of CYP1A and CYP1B1 by FICZ were 0.6 and 0.5nM compared to 72-h EC(50) values of 2.3 and 2.7nM for PCB126, indicating that in zebrafish embryos FICZ is a more potent inducer than PCB126. FICZ at 10nM was able to completely displace binding of 2,3,7,8-tetrachloro-1,6[(3)H]-dibenzo-p-dioxin to in vitro-expressed zebrafish AHR2 and AHR1B. Inhibition of AHR2 translation in zebrafish embryos by an AHR2-specific morpholino antisense oligonucleotide decreased the induction of CYP1A and CYP1B1 by FICZ and by PCB126. Together, these results demonstrate that FICZ is a potent AHR agonist in zebrafish, inducing expression of multiple CYP1 genes largely through AHR2. Evolutionary conservation of the response to FICZ is consistent with a possible role as an endogenous signaling molecule acting through the AHR.

  • 12. Li, Zhi-Hua
    et al.
    Velisek, Josef
    Zlabek, Vladimir
    Grabic, Roman
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Machova, Jana
    Kolarova, Jitka
    Randak, Tomas
    Hepatic antioxidant status and hematological parameters in rainbow trout, Oncorhynchus mykiss, after chronic exposure to carbamazepine2010Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 183, nr 1, s. 98-104Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recently, residual pharmaceuticals are generally recognized as relevant sources of aquatic environmental pollutants. However, the toxicological effects of these contaminants have not been adequately researched. In this study, the chronic toxic effect of carbamazepine (CBZ), an anticonvulsant drug commonly present in surface and ground water, on hepatic antioxidant status and hematological parameters of rainbow trout were investigated. Fish were exposed at sublethal concentrations of CBZ (1.0mug/l, 0.2mg/l and 2.0mg/l) for 7, 21 and 42 days. Compared to the control group, fish exposed at higher concentration (0.2mg/l or 2.0mg/l) of CBZ showed significantly higher levels of hemoglobin, ammonia and glucose, and significantly higher plasma enzymes activities. During the exposure duration, erythrocyte count, hematocrit, mean erythrocyte hemoglobin, mean erythrocyte volume, mean color concentration and total protein content in all groups were not significantly different. At the highest test concentration (2.0mg/l) of CBZ, oxidative stress was apparent as reflected by the significant higher lipid peroxidation and protein carbonyl levels in liver after 42 days exposure, associated with an inability to induce antioxidant enzymes activities including superoxide dismutase, glutathione peroxidase and glutathione reductase. After 42 days exposure, reduced glutathione level was significantly decreased in the fish exposed at 0.2mg/l CBZ, compared with the control. In short, CBZ-induced physiological and biochemical responses in fish were reflected in the oxidant stress indices and hematological parameters. These results suggest that hepatic antioxidant responses and hematological parameter could be used as potential biomarkers for monitoring residual pharmaceuticals present in aquatic environment.

  • 13. Li, Zhi-Hua
    et al.
    Zlabek, Vladimir
    Grabic, Roman
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Li, Ping
    Machova, Jana
    Velisek, Josef
    Randak, Tomas
    Effects of exposure to sublethal propiconazole on intestine-related biochemical responses in rainbow trout, Oncorhynchus mykiss2010Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 185, nr 3, s. 241-246Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effect of long-term (30 days) exposure to PCZ (0.2, 50, and 500 microg l(-1)) on intestine-related biochemical markers in rainbow trout was investigated. Multiple biomarkers were measured, including digestive enzymes (proteolytic enzymes and amylase), antioxidant responses (TBARS, CP, SOD, CAT, GR and GPx) and energy metabolic parameters (RNA/DNA ratio, Na(+)-K(+)-ATPase). Exposure to 500 microg l(-1) PCZ led to significantly inhibited (p<0.01) proteolytic enzyme and amylase activity. Activities of the antioxidant enzymes SOD, CAT, and GPx gradually increased at lower PCZ concentrations (0.2 and 50 microg l(-1)). At the highest concentration (500 microg l(-1)), oxidative stress was apparent as significant higher (p<0.05) lipid peroxidation and protein carbonyls, associated with an inhibition of antioxidant enzymes activity. Moreover, energy metabolic parameters (RNA/DNA ratio, Na(+)-K(+)-ATPase) were significantly inhibited (p<0.01) in the intestines of fish exposed to 500 microg l(-1) PCZ, compared with controls. We suggest that long-term exposure to PCZ could result in several responses in intestine-related biochemical markers, which potentially could be used as indicators for monitoring residual PCZ present in the aquatic environment.

  • 14.
    Lind, Monica
    et al.
    Institute of Environmental Medicine, Karolinska Institutet.
    Johansson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönn, Monika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Arbets- och miljömedicin.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Subclinical Hypervitaminosis A in Rat: Measurements of bone mineral density (BMD) do not reveal adverse skeletal changes2006Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 159, nr 1, s. 73-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

  • 15. Lind, P. M.
    et al.
    Johansson, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönn, M.
    Melhus, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Subclinical hypervitaminosis A in rat: measurements of bone mineral density (BMD) do not reveal adverse skeletal changes2006Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 159, nr 1, s. 73-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

  • 16. Luecke, S.
    et al.
    Wincent, E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Backlund, M.
    Rannug, U.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Rannug, A.
    Cytochrome P450 1A1 gene regulation by UVB involves crosstalk between the aryl hydrocarbon receptor and nuclear factor kappa B2010Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 184, nr 3, s. 466-473Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 17.
    Lundgren, Bo
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Meijer, J
    Birberg, W
    Pilotti, A
    Depierre, J W
    Induction of cytosolic and microsomal epoxide hydrolases in mouse liver by peroxisome proliferators, with special emphasis on structural analogues of 2-ethylhexanoic acid.1988Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 68, nr 3-4Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Using dietary administration, mice were exposed to eight substances known to cause peroxisome proliferation (i.e. clofibrate clofibric acid, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, nafenopin, ICI-55.897, S-8527 and Wy-14.643) or the related substance p-chlorophenoxyacetic acid (group A). Other animals received di(2-ethylhexyl)phthalate, mono(2-ethylhexyl)phthalate, 2-ethylhexanoic acid, or one of 12 other metabolically and/or structurally related compounds (group B). The effects of these treatments on liver cytosolic and microsomal epoxide hydrolases, microsomal cytochrome P-450, cytosolic glutathione transferase activity, the liver-somatic index and the protein contents of the microsomal and cytosolic fractions prepared from liver were subsequently monitored. In general, peroxisome proliferation was accompanied by increases in cytosolic epoxide hydrolase activity. Many peroxisome proliferators also caused increases in microsomal epoxide hydrolase activity, although the correlation was poorer in this case. Immunochemical quantitation by radial immunodiffusion demonstrated that the increases observed in both of these enzyme activities reflected equivalent increases in enzyme protein, i.e. that induction truly occurred. Induction of total microsomal cytochrome P-450 was obtained after dietary exposure to clofibrate, clofibric acid, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid, nafenopin, Wy-14.643, di(2-ethylhexyl)phthalate and di(2-ethylhexyl)phosphate. The most pronounced effects on cytosolic glutathione transferase activity were the decreases obtained after treatment with clofibrate, clofibric acid and Wy-14.643. Our results, together with those reported by others, suggest that the processes of peroxisome proliferation and induction of cytosolic epoxide hydrolase are intimately related. One possible explanation for this is presented.

  • 18. Mattsson, Ase
    et al.
    Jernstrom, Bengt
    Cotgreave, Ian A.
    Bajak, Edyta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    H2AX phosphorylation in A549 cells induced by the bulky and stable DNA adducts of benzo[a]pyrene and dibenzo[a,l]pyrene diol epoxides2009Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 177, nr 1, s. 40-47Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Early events in the cellular response to DNA damage, such as double strand breaks, rely on lesion recognition and activation of proteins involved in maintenance of genomic stability. One important component of this process is the phosphorylation of the histone variant H2AX. To investigate factors explaining the variation in carcinogenic potency between different categories of polycyclic aromatic hydrocarbons (PAHs). we have studied the phosphorylation of H2AX (H2AX gamma). A549 cells were exposed to benzo[a]pyrene diol epoxide [(+)-anti-BPDE] (a bay-region PAH) and dibenzo[a,l]pyrene diol epoxide [(-)-anti-DBPDE] (a fjord-region PAH) and H2AX gamma was studied using immunocytochemistry and Western blot. Hydrogen peroxide (H2O2) was used to induce oxidative DNA damage and strand breaks. As showed with single cell gel electrophoresis, neither of the diol epoxides resulted in DNA strand breaks relative to H2O2. Visualisation of H(2)AX gamma formation demonstrated that the proportion of cells exhibiting H2AX gamma staining at 1 h differed between BPDE, 40% followed by a decline, and DBPDE, <10% followed by an increase. With H2O2 treatment, almost all cells demonstrated H(2)AX gamma at 1 h. Western blot analysis of the H2AX gamma formation also showed concentration and time-dependent response patterns. The kinetics of H2AX gamma formation correlated with the previously observed kinetics of elimination of BPDE and DBPDE adducts. Thus, the extent of H2AX gamma formation and persistence was related to both the number of adducts and their structural features.

  • 19.
    Mazari, Aslam M. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Hegazy, Usama M.
    Mannervik, Bengt
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi.
    Identification of new inhibitors for human hematopoietic prostaglandin D-2 synthase among FDA-approved drugs and other compounds2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 229, s. 91-99Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Hematopoietic prostaglandin D-2 synthase (HPGDS) is a member of the Sigma class glutathione transferases (GSTs) catalyzing the isomerization of prostaglandin H-2 to prostaglandin D-2, a mediator of allergy and inflammation responses. Selective inhibitors of human HPGDS are expected to be of therapeutic importance in relieving symptoms related to allergy and asthma. Hence, a collection of diverse FDA-approved compounds was screened for potential novel applications as inhibitors of HPGDS. Methods: The catalytic activity of purified HPGDS was used for inhibition studies in vitro. Results: Our inhibition studies revealed 23 compounds as effective inhibitors of HPGDS with IC50 values in the low micromolar range. Erythrosine sodium, suramin, tannic acid and sanguinarine sulfate were characterized with IC50 values of 0.2, 0.3, 0.4, and 0.6 mu M, respectively. Kinetic inhibition analysis showed that erythrosine sodium is a nonlinear competitive inhibitor of HPGDS, while suramin, tannic acid and sanguinarine sulfate are linear competitive inhibitors. Conclusion: The results show that certain FDA-approved compounds may have pharmacological effects not previously realized that warrant further consideration in their clinical use.

  • 20.
    Motwani, Hitesh
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Eriksson, Lars
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Göpfert, Lisa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Larsen, Kristian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Reaction kinetic studies for comparison of mutagenic potency between butadiene monoxide and glycidamide2018Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 288, s. 57-64Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    DNA adducts can be formed from covalent binding of electrophilic reactive compounds to the nucleophilic Nand O-atoms of the biomolecule. The O-sites on DNA, with nucleophilic strength (n) of ca. 2, is recognized as a critical site for mutagenicity. Characterization of the reactivity of electrophilic compounds at the O-sites can be used to predict their mutagenic potency in relative terms. In the present study, reaction kinetic experiments were performed for butadiene monoxide (BM) in accordance with the Swain-Scott relation using model nucleophiles representing N- and O-sites on DNA, and earlier for glycidamide (GA) using a similar approach. The epoxide from the kinetic experiments was trapped by cob(I)alamin, resulting in formation of an alkylcobalamin which was analyzed by liquid chromatography tandem mass spectrometry. The Swain-Scott relationship was used to determine selectivity constant (s) of BM and GA as 0.86 and 1.0, respectively. The rate constant for the reaction at n of 2 was extrapolated to 0.023 and 0.038M(-1) h(-1) for BM and GA, respectively, implying a higher mutagenic potency per dose unit of GA compared to BM. The reaction kinetic parameters associated with mutagenic potency were also estimated by a density functional theory approach, which were in accordance to the experimental determined values. These types of reaction kinetic measures could be useful in development of a chemical reactivity based prediction tool that could aid in reduction of animal experiments in cancer risk assessment procedures for relative mutagenicity.

  • 21. Musdal, Yaman
    et al.
    Hegazy, Usama M.
    Aksoy, Yasemin
    Mannervik, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-12013Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 205, nr 1, s. 53-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Glutathione transferase P1-1 (GST P1-1) is often overexpressed in tumor cells and is regarded as a contributor to their drug resistance. Inhibitors of GST P1-1 are expected to counteract drug resistance and may therefore serve as adjuvants in the chemotherapy of cancer by increasing the efficacy of cytostatic drugs. Finding useful inhibitors among compounds used for other indications would be a shortcut to clinical applications and a search for GST P1-1 inhibitors among approved drugs and other compounds was therefore conducted. Methods: We tested 1040 FDA-approved compounds as inhibitors of the catalytic activity of purified human GST P1-1 in vitro. Results: We identified chlorophyllide, merbromine, hexachlorophene, and ethacrynic acid as the most effective GST P1-1 inhibitors with IC50 values in the low micromolar range. For comparison, these compounds were even more potent in the inhibition of human GST A3-3, an enzyme implicated in steroid hormone biosynthesis. In distinction from the other inhibitors, which showed conventional inhibition patterns, the competitive inhibitor ethacrynic acid elicited strong kinetic cooperativity in the glutathione saturation of GST P1-1. Apparently, ethacrynic acid serves as an allosteric inhibitor of the enzyme. Conclusion and practical implications: In their own right, the compounds investigated are less potent than desired for adjuvants in cancer chemotherapy, but the structures of the most potent inhibitors could serve as leads for the synthesis of more efficient adjuvants. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  • 22.
    Musdal, Yaman
    et al.
    Uppsala University, Sweden; Hacettepe University, Turkey.
    Hegazy, Usama M.
    Aksoy, Yasemin
    Mannervik, Bengt
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för neurokemi. Uppsala University, Sweden.
    FDA-approved drugs and other compounds tested as inhibitors of human glutathione transferase P1-12013Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 205, nr 1, s. 53-62Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Glutathione transferase P1-1 (GST P1-1) is often overexpressed in tumor cells and is regarded as a contributor to their drug resistance. Inhibitors of GST P1-1 are expected to counteract drug resistance and may therefore serve as adjuvants in the chemotherapy of cancer by increasing the efficacy of cytostatic drugs. Finding useful inhibitors among compounds used for other indications would be a shortcut to clinical applications and a search for GST P1-1 inhibitors among approved drugs and other compounds was therefore conducted. Methods: We tested 1040 FDA-approved compounds as inhibitors of the catalytic activity of purified human GST P1-1 in vitro. Results: We identified chlorophyllide, merbromine, hexachlorophene, and ethacrynic acid as the most effective GST P1-1 inhibitors with IC50 values in the low micromolar range. For comparison, these compounds were even more potent in the inhibition of human GST A3-3, an enzyme implicated in steroid hormone biosynthesis. In distinction from the other inhibitors, which showed conventional inhibition patterns, the competitive inhibitor ethacrynic acid elicited strong kinetic cooperativity in the glutathione saturation of GST P1-1. Apparently, ethacrynic acid serves as an allosteric inhibitor of the enzyme. Conclusion and practical implications: In their own right, the compounds investigated are less potent than desired for adjuvants in cancer chemotherapy, but the structures of the most potent inhibitors could serve as leads for the synthesis of more efficient adjuvants.

  • 23. Olsson, U
    et al.
    Garberg, P
    Lundgren, Bo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    Andersson, K
    Hultenby, K
    Bergstrand, A
    Eriksson, A M
    Högberg, J
    DePierre, J W
    The involvement of selenium in peroxisome proliferation caused by dietary administration of clofibrate to rats.1992Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 85, nr 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The effects of dietary treatment with clofibrate (0.5% w/w for 10 days) on the livers of selenium-deficient male rats were examined. The peroxisome proliferation (as determined by electron microscopy) in the livers of selenium-deficient animals was much less pronounced than in the case of selenium-adequate rats and no increase in peroxisomal fatty acid beta-oxidation (assayed both as antimycin-insensitive palmitoyl-CoA oxidation and lauroyl-CoA oxidase activity) was observed in the deficient animals. On the other hand, in selenium-deficient rats clofibrate caused increases in the specific activity of microsomal lauric acid omega- and omega-1-hydroxylation and an apparent change in mitochondrial size, seen as a redistribution of mitochondria from the 600 x g(av) pellet to the 10,000 x g(av) pellet, which were approximately 50% as great as the corresponding effects on control animals. Obviously, then, these three different effects of clofibrate are not strictly coupled and may involve at least partially distinct underlying mechanisms. Initial experiments demonstrated that peroxisome proliferation could be obtained by exposing primary hepatocyte cultures derived from selenium-deficient rats to clofibric acid (an in vivo hydrolysis product of clofibrate which is the proximate peroxisome proliferator), nafenopin or mono(2-ethylhexyl)phthalate. This finding suggests that selenium deficiency does not have a direct influence on the basic process(es) underlying peroxisome proliferation, but rather has indirect effects, influencing, for example, the pharmacokinetics of clofibrate and/or hormonal factors.

  • 24. Ostberg, Linus J.
    et al.
    Persson, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräknings- och systembiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hoog, Jan-Olov
    The mammalian alcohol dehydrogenase genome shows several gene duplications and gene losses resulting in a large set of different enzymes including pseudoenzymes2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 234, s. 80-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mammalian alcohol dehydrogenase (ADH) is a protein family divided into six classes and the number of known family members is increasing rapidly. Several primate genomes are completely analyzed for the ADH region, where higher primates (human and hominoids) have seven genes of classes ADH1-ADH5. Within the group of non-hominoids apes there have been further duplications and species with more than the typical three isozymic forms for ADH1 are present. In contrast there are few completely analyzed ADH genomes in the non-primate group of mammals, where an additional class has been identified, ADH6, that has been lost during the evolution of primates. In this study 85 mammalian genomes with at least one ADH gene have been compiled. In total more than 500 ADH amino acid sequences were analyzed for patterns that distinguish the different classes. For ADH1-ADH4 intensive investigations have been performed both at the functional and at structural levels. However, a corresponding functional protein to the ADH5 gene, which is found in most ADH genomes, has never been detected. The same is true for ADH6, which is only present in non-primates. The entire mammalian ADH family shows a broad spectrum of gene duplications and gene losses where the numbers differ from six genes (most non-primate mammals) up to ten genes (vole). Included in these sets are examples of pseudogenes and pseudoenzymes.

  • 25.
    Ostberg, Linus J.
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan. Karolinska Institute, Sweden .
    Stromberg, Patrik
    Karolinska Institute, Sweden .
    Hedberg, Jesper J.
    Karolinska Institute, Sweden .
    Persson, Bengt
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Hoog, Jan-Olov
    Karolinska Institute, Sweden .
    Analysis of mammalian alcohol dehydrogenase 5 (ADH5): Characterisation of rat ADH5 with comparisons to the corresponding human variant2013Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 202, nr 1-3, s. 97-103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alcohol dehydrogenase 5 (ADH5) is a member of the mammalian alcohol dehydrogenase family of yet undefined functions. ADH5 was first identified at the DNA level in human and deer mouse. A rat alcohol dehydrogenase structure of similar type has been isolated at the cDNA level using human ADH5 as a screening probe, where the rat cDNA structure displayed several atypical properties. mRNA for rat ADH5 was found in multiple tissues, especially in the kidney. In vitro translation experiments indicated that rat ADH5 is expressed as efficiently as ADH1 and furthermore, rat ADH5 was readily expressed in COS cells fused to Green Fluorescent Protein. However, no soluble ADH5 protein could be heterologously expressed in Escherichia coil cells with expression systems successfully used for other mammalian ADHs, including fused to glutathione-S-transferase. Molecular modelling of the enzyme indicated that the protein does not fold in a productive way, which can be the explanation why no stable and active ADH5 has been isolated. These results indicate that ADH5, while readily expressed at the mRNA level, does not behave similarly to other mammalian ADHs investigated. The results, in vitro and in silico, suggest an unstable ADH5 structure, which can explain for why no active and stable protein can be isolated. Further possibilities are conceivable: the ADH5 protein may have to interact with a stabiliser, or the gene is actually a pseudogene.

  • 26.
    Persson, Bengt
    et al.
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Kallberg, Y.
    Dept. of Med. Biochem./Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Oppermann, U.
    Dept. of Med. Biochem./Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Jornvall, H.
    Jörnvall, H., Dept. of Med. Biochem./Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Coenzyme-based functional assignments of short-chain dehydrogenases/reductases (SDRs)2003Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 143-144, s. 271-278Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Short-chain dehydrogenases/reductases (SDRs) are enzymes of great functional diversity. In spite of a residue identity of only 15-30%, the folds are conserved to a large extent, with specific sequence motifs detectable. We have developed an assignment scheme based on these motifs and detect five families. Only two of these were known before, called 'Classical' and 'Extended', but are now distinguished at a further level based on patterns of charged residues in the coenzyme-binding region, giving seven subfamilies of classical SDRs and three subfamilies of extended SDRs. Three further families are novel entities, denoted 'Intermediate', 'Divergent' and 'Complex', encompassing short-chain alcohol dehydrogenases, enoyl reductases and multifunctional enzymes, respectively. The assignment scheme was applied to the genomes of human, mouse, D. melanogaster, C. elegans, A. thaliana and S. cerevisiae. In the animal genomes, genes corresponding to the extended SDRs amount to around one quarter or less of the total number of SDR genes, while in those of A. thaliana and S. cerevisiae, the extended members constitute about 40% of the SDR forms. The NAD(H)-dependent SDRs are about equally many as the NADP(H)-dependent ones in human, mouse and plant, while the proportions of NAD(H)-dependent enzymes are much lower in fruit fly, worm and yeast. We also find that NADP(H) is the preferred coenzyme among most classical SDRs, while NAD(H) is that preferred among most extended SDRs. © 2002 Elsevier Science Ireland Ltd. All rights reserved.

  • 27.
    Persson, Bengt
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Kallberg, Yvonne
    Karolinska Institute, Sweden .
    Classification and nomenclature of the superfamily of short-chain dehydrogenases/reductases (SDRs)2013Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 202, nr 1-3, s. 111-115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The short-chain dehydrogenases/reductases (SDRs) constitute one of the largest protein superfamilies known today. The members are distantly related with typically 20-30% residue identity in pair-wise comparisons. Still, all hitherto structurally known SDRs present a common three-dimensional structure consisting of a Rossmann fold with a parallel beta sheet flanked by three helices on each side. Using hidden Markov models (HMMs), we have developed a semi-automated subclassification system for this huge family. Currently, 75% of all SDR forms have been assigned to one of the 464 families totalling 122,940 proteins. There are 47 human SDR families, corresponding to 75 genes. Most human SDR families (35 families) have only one gene, while 12 have between 2 and 8 genes. For more than half of the human SDR families, the three-dimensional fold is known. The number of SDR members increases considerably every year, but the number of SDR families now starts to converge. The classification method has paved the ground for a sustainable and expandable nomenclature system. Information on the SDR superfamily is continuously updated at http://sdr-enzymes.org/.

  • 28.
    Persson, Bengt
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Kallberg, Yvonne
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik. Linköpings universitet, Tekniska högskolan.
    Bray, James E
    Oxford University .
    Bruford, Elspeth
    European Bioinformation Institute.
    Dellaporta, Stephen L
    Yale University.
    Favia, Angelo D
    University of Barcelona.
    Jornvall, Hans
    Karolinska Institute.
    Kavanagh, Kathryn L
    Oxford University .
    Kedishvili, Natalia
    University of Alabama.
    Kisiela, Michael
    University Medical School Schleswig Holstein.
    Maserk, Edmund
    University Medical School Schleswig Holstein.
    Mindnich, Rebekka
    University of Pennsylvania.
    Orchard, Sandra
    University of Pennsylvania.
    Thornton, Janet M
    German Research Centre Environmental Health.
    Oppermann , Udo
    Oxford University .
    The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative2009Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 178, nr 1-3, s. 94-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Short-chain dehydrogenases/reductases (SDR) constitute one of the largest enzyme superfamilies with presently over 46,000 members. In phylogenetic comparisons, members of this superfamily show early divergence where the majority have only low pairwise sequence identity, although sharing common structural properties. The SDR enzymes are present in virtually all genomes investigated, and in humans over 70 SDR genes have been identified. In humans, these enzymes are involved in the metabolism of a large variety of compounds, including steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. It is now clear that SDRs represent one of the oldest protein families and contribute to essential functions and interactions of all forms of life. As this field continues to grow rapidly, a systematic nomenclature is essential for future annotation and reference purposes. A functional subdivision of the SDR superfamily into at least 200 SDR families based upon hidden Markov models forms a suitable foundation for such a nomenclature system, which we present in this paper using human SDRs as examples.

  • 29.
    Pradhan, Ajay
    et al.
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Asnake, Solomon
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Kharlyngdoh, Joubert Banjop
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Modig, Carina
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    Olsson, Per-Erik
    Örebro universitet, Institutionen för naturvetenskap och teknik.
    In silico and biological analysis of anti-androgen activity of the brominated flame retardants ATE, BATE and DPTE in zebrafish2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 233, s. 35-45Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The brominated flame retardants (BFRs) 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH or DBE-DCBH) and allyl 2,4,6-tribromophenyl ether (ATE or TBP-AE) are alternative BFRs that have been introduced to replace banned BFRs. TBECH is a potential endocrine disrupter in human, chicken and zebrafish and in a recent study we showed that ATE, along with the structurally similar BFR 2,3-dibromopropyl 2,4,6-tribromophenyl ether (DPTE or TBP-DBPE) and its metabolite 2-bromoallyl 2,4,6-tribromophenyl ether (BATE or TBP-BAE) are potential endocrine and neuronal disrupters in human. In this study we analyzed ATE, BATE and DPTE for zebrafish androgen receptor (zAR) modulating properties. In silico analysis with two softwares, Molecular Operating Environment (MOE) and Internal Coordinate Mechanics (ICM), showed that ATE, BATE and DPTE bind to zAR. In vitro AR activation assay revealed that these three BFRs down-regulate 11-ketotestosterone (KT) mediated zAR activation. Exposure to 10 mu M DPTE resulted in reduced hatching success and like TBECH, BATE and DPTE at 10 mu M also had teratogenic properties with 20% and 50% back-bone curvature respectively. Gene transcription analysis in zebrafish embryos as well as in juveniles showed down-regulation of the androgen receptor and androgen response genes, which further support that these BFRs are androgen antagonists and potential endocrine disrupting compounds. Genes involved in steroidogenesis were also down-regulated by these BFRs. In view of this, the impact of these BFRs on humans and wildlife needs further analysis.

  • 30.
    Terman, Alexei
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Geriatrik.
    Gustafsson, Bertil
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Patologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.
    Brunk, Ulf
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    The lysosomal-mitochondrial axis theory of postmitotic aging and cell death2006Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 163, nr 1-2, s. 29-37Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aging (senescence) is characterized by a progressive accumulation of macromolecular damage, supposedly due to a continuous minor oxidative stress associated with mitochondrial respiration. Aging mainly affects long-lived postmitotic cells, such as neurons and cardiac myocytes, which neither divide and dilute damaged structures, nor are replaced by newly differentiated cells. Because of inherent imperfect lysosomal degradation (autophagy) and other self-repair mechanisms, damaged structures (biological "garbage") progressively accumulate within such cells, both extra- and intralysosomally. Defective mitochondria and aggregated proteins are the most typical forms of extralysosomal "garbage", while lipofuscin that forms due to iron-catalyzed oxidation of autophagocytosed or heterophagocytosed material, represents intralysosomal "garbage". Based on findings that autophagy is diminished in lipofuscin-loaded cells and that cellular lipofuscin content positively correlates with oxidative stress and mitochondrial damage, we have proposed the mitochondrial-lysosomal axis theory of aging, according to which mitochondrial turnover progressively declines with age, resulting in decreased ATP production and increased oxidative damage. Due to autophagy of ferruginous material, lysosomes contain a pool of redox-active iron, which makes these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes releases hydrolytic enzymes to the cytosol, eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult), while chelation of the intralysosomal pool of redox-active iron prevents these effects. In relation to the onset of oxidant-induced apoptosis, but after the initiating lysosomal rupture, cytochrome c is released from mitochondria and caspases are activated. Mitochondrial damage follows the release of lysosomal hydrolases, which may act either directly or indirectly, through activation of phospholipases or pro-apoptotic proteins such as Bid. Additional lysosomal rupture seems to be a consequence of a transient oxidative stress of mitochondrial origin that follows the attack by lysosomal hydrolases and/or phospholipases, creating an amplifying loop system. © 2006 Elsevier Ireland Ltd. All rights reserved.

  • 31. Thors, L.
    et al.
    Koch, M.
    Wigenstam, E.
    Koch, B.
    Hagglund, L.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Comparison of skin decontamination efficacy of commercial decontamination products following exposure to VX on human skin2017Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 273, s. 82-89Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The decontamination efficacy of four commercially available skin decontamination products following exposure to the nerve agent VX was evaluated in vitro utilizing a diffusion cell and dermatomed human skin. The products included were Reactive Skin Decontamination Lotion (RSDL), the Swedish decontamination powder 104 (PS104), the absorbent Fuller's Earth and the aqueous solution alldecontMED. In addition, various decontamination procedures were assessed to further investigate important mechanisms involved in the specific products, e.g. decontamination removal from skin, physical removal by sponge swabbing and activation of degradation mechanisms. The efficacy of each decontamination product was evaluated 5 or 30 min after dermal application of VX (neat or diluted to 20% in water).

    The RSDL-lotion was superior in reducing the penetration of VX through human skin, both when exposed as neat agent and when diluted to 20% in water. Swabbing with the RSDL-sponge during 2 min revealed decreased efficacy compared to applying the RSDL-lotion directly on the skin for 30 min. Decontamination with Fuller's Earth and alldecontMED significantly reduced the penetration of neat concentration of VX through human skin. PS104-powder was insufficient for decontamination of VX at both time-points, independently of the skin contact time of PS104. The PS104-slurry (a mixture of PS104-powder and water), slightly improved the decontamination efficacy. Comparing the time-points for initiated decontamination revealed less penetrated VX for RSDL and Fuller's Earth when decontamination was initiated after 5 min compared to 30 min post-exposure, while alldecontMED displayed similar efficacy at both time-points. Decontamination by washing with water only resulted in a significant reduction of penetrated VX when washing was performed 5 min after exposure, but not when decontamination was delayed to 30 min post-exposure of neat VX.

    In conclusion, early initiated decontamination with the RSDL-lotion, containing both absorption and degrading properties, allowed to act on skin for 30 min was superior in preventing VX from penetrating human skin. Adding water during decontamination resulted in increased penetration of neat VX, however, water in the decontaminant removal process did not influence the decontamination efficacy. From our study on commercially available decontaminants, it is recommended that future product developments should include both strong absorbents and efficient nerve agent degrading components.

  • 32.
    Toft, E
    et al.
    Wallenberg Laboratory, Stockholm University, Sweden.
    Becedas, L
    Wallenberg Laboratory, Stockholm University, Sweden.
    Söderström, Mats
    Wallenberg Laboratory, Stockholm University, Sweden.
    Lundqvist, A
    Wallenberg Laboratory, Stockholm University, Sweden.
    Depierre, J W
    Wallenberg Laboratory, Stockholm University, Sweden.
    Glutathione transferase isoenzyme patterns in the rat ovary1997Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 108, nr 1-2, s. 79-93Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study was designed to investigate the expression of different isoenzymes of glutathione transferase (GST) in the rat ovary and to follow possible changes in the pattern of expression during maturation and the different stages of the oestrus cycle. The GST subunits present in the rat ovary (as analyzed by HPLC of affinity-purified GSTs) were A3, A4, M1, M2, M3 and P1. The most abundant subunit in the ovary was A3, but the mu enzymes demonstrated the largest increase (3.5-fold) when the mature ovary was compared to the immature organ. An overall decrease in GST isoenzyme content during dioestrus was observed, but there were no other recurrent changes during the oestrus cycle. Treatment of immature rats with pregnant mare's serum gonadotropin clearly demonstrated that the mu and alpha isoenzymes are up-regulated by gonadotropin stimulation, i.e. a 4-6 fold increase was seen. This treatment also elevated the P1 subunit 3-fold. At present, it is only possible to speculate concerning the mechanism(s) underlying these variations in ovarian GST expression in connection with hormonal changes. The functional significance of these variations is not yet known.

  • 33.
    Zhang, Wei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Modén, Olof
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Mannervik, Bengt
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Differences among allelic variants of human glutathione transferase A2-2 in the activation of azathioprine2010Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 186, nr 2, s. 110-117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Azathioprine has been clinically used for decades in connection with organ transplantation, autoimmune disease, and treatment of cancer. Toxic side-reactions are common and have been linked to the liberation of excessively high concentrations of 6-mercaptopurine and corresponding toxic metabolites. An allelic variant of thiopurine methyltransferase with low activity is associated with elevated concentrations of 6-mercaptopurine. However, other genetic markers remain to be identified in order to fully account for adverse reactions and efficacy failure. In the present study, we studied the five known allelic variants of human glutathione transferase A2-2 (GST A2-2) (EC2.5.1.18), abundantly expressed in liver and efficiently catalyzing the bioactivation of azathioprine to release 6-mercaptopurine. All five variants exhibited high activity with azathioprine, but allelic variant E of GST A2-2 displayed a 3-4-fold elevated catalytic efficiency compared to the other variants. High GST activity can lead to overproduction of 6-mercaptopurine, and the nature of the multiple forms of GSTs in a patient will obviously affect the metabolism of azathioprine. In addition to GST A2-2, the polymorphic GST M1-1 is also highly active with azathioprine. Considering our findings, it appears that the genotypic and phenotypic variations in the GST complement may influence the presentation of adverse reactions in patients treated with azathioprine. Clinical trials will be required to clarify the impact of the GST expression in comparison with the established biomarker thiopurine methyltransferase as predictors of adverse reactions.

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