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  • 1. 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]pyrene2015Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, s. 164-173Artikel i tidskrift (Refereegranskat)
    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. 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 1C32017Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 276, s. 194-202Artikel i tidskrift (Refereegranskat)
    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.

  • 3. 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 carbamazepine2010Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 183, nr 1, s. 98-104Artikel i tidskrift (Refereegranskat)
    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.

  • 4. 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 mykiss2010Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 185, nr 3, s. 241-246Artikel i tidskrift (Refereegranskat)
    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.

  • 5. 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 skin2017Ingår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 273, s. 82-89Artikel i tidskrift (Refereegranskat)
    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.

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