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  • 1.
    Abelson, Klas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Försöksdjursvetenskap.
    Höglund, Urban
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Försöksdjursvetenskap.
    Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats2002Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 90, nr 4, s. 187-192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Abstract:Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10–300 μg/kg) and atropine (0.1, 10, 5000 μg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2–C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 μg/kg), or subcutaneously with oxotremorine (30, 100, 300 μg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 μg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 μg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.

  • 2. Barg, Sebastian
    Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells.2003Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 92, nr 1, s. 3-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In pancreatic B- and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca2+-influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca2+-influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (<1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further "priming" for release by several ATP- and Ca2+-dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca2+-channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.

  • 3.
    Carlsson, Carina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Ekotoxikologi.
    Fredriksson, Anders
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Ekotoxikologi.
    Brandt, Ingvar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Ekotoxikologi.
    2,6-Dichlorophenyl methylsulphone induced behavioural impairments in rats and mice in relation to olfactory mucosal metaplasia2003Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 93, nr 4, s. 156-168Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    2,6-Dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) induces persistent olfactory mucosal metaplasia and a strong glial fibrillary acidic protein increase in the olfactory bulb of mice. Furthermore, 2,6-diClPh-MeSO2 gives rise to a long-lasting hyperactivity along with an impaired radial arm maze performance. To study cause-effect relationships, olfactory mucosal histopathology, glial fibrillary acidic protein induction and neurobehavioural deficits were re-examined in mice and rats of both sexes given a single intraperitoneal dose of 2,6-diClPh-MeSO2 (16 and 65 mg/kg). There was a clear difference in the character of the olfactory mucosal lesions in the two species. In mice, an extensive metaplasia characterised by severe fibrosis, cartilage and bone formation accompanied with large polyps filling the nasal lumen was confirmed. In rats, a dose-dependent weak metaplasia with patchy loss of olfactory epithelium was observed three weeks after dosing, preferentially at the dorsal meatus, nasal septum, and the tips of the middle ethmoturbinates. Large areas of intact olfactory epithelium remained in all animals, particularly in the low dose rats. In both species, 2,6-diClPh-MeSO2 gave rise to significantly increased motor-activities, impaired performance in the radial arm maze, and glial fibrillary acidic protein-induction. Only rats showed hyperactivity at the low dose. Performance in the Morris water maze was unaffected in rats of both sexes indicating that a general impairment in spatial learning could not be supported. We propose that the observed hyperactivity and radial arm maze acquisition deficits originated from a direct effect of 2,6-diClPh-MeSO2 in the brain rather than being a consequence of the olfactory mucosal lesion.

  • 4. EWALD, G
    et al.
    SUNDIN, Peter
    ATP LEAKAGE FROM ELD CELLS AFTER EXPOSURE TO STEARIC, MONOCHLOROSTEARIC, DICHLOROSTEARIC, AND OLEIC ACIDS1993Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 73, nr 3, s. 159-162Artikel i tidskrift (Refereegranskat)
  • 5. Gustafson-Svard, C
    et al.
    Akesson-Nilsson, G
    Mattsson, M
    Sundin, Peter
    Wesen, C
    Removal of xenobiotic dichalorostearic acid from phospholipids and neutral lipids in cultured human cell lines by beta-oxidation and secretion of dichloromyristic acid2001Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 89, nr 1, s. 56-64Artikel i tidskrift (Refereegranskat)
  • 6.
    Johansson, Maria
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för evolutionsbiologi, Ekotoxikologi.
    Larsson, C.
    Bergman, Å.
    Lund, B-O
    Structure-activity relationship for inhibition of CYP11B1-dependent glucocorticoid synthesis in Y1 cells by aryl methyl sulfones1998Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 83, nr 5, s. 225-230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The effects of xenobiotics on CYP11B1-dependent corticosterone synthesis (11 beta-hydroxylase) in mouse adrenocortical Y1 cells were studied. 3-Methylsulfonyl-2,2-bis(4-chlorophenyl)-1,1-dichloroethene (MeSO2-DDE) and some methylsulfonyl polychlorinated biphenyls (MeSO2-PCB) inhibited the corticosterone synthesis, whereas PCBs or DDE did not. This indicates a crucial role of the methyl sulfone group for this inhibitory effect. Kinetic analyses of MeSO2-DDE and the two most potent MeSO2-PCBs were conducted using Lineweaver-Burk double-reciprocal plots. The data showed a competitive inhibition of CYP11B1 by the compounds, with apparent inhibitory constants (Ki) of 1.6, 4.6, and 6.7 microM for MeSO2-DDE, 4-MeSO2-2,3,6,4'-tetrachlorobiphenyl, and 4-MeSO2-2,3,6,3',4'-pentachlorobiphenyl, respectively. For comparison, the substrate K(m) was 3.5 microM in the cells, and metyrapone and ketoconazole had apparent Ki-values of 0.8 and 0.04 microM, respectively. In contrast to all previously known inhibitors of CYP11B1, the aryl methyl sulfones are the first examples of CYP11B1 inhibitors not being heterocyclic amines or steroids. The aryl methyl sulfones are widespread environmental pollutants and their inhibition of CYP11B1 constitutes another potential mechanism for endocrine disruption. Their influence on the synthesis of adrenocortical hormones thus merits further interest.

  • 7.
    Lind, Anna-Britta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Klinisk farmakologi.
    Wadelius, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Darj, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Finnström, Niklas
    Lundgren, Stefan
    Rane, Anders
    Gene expression of cytochrome P450 1B1 and 2D6 in leukocytes in human pregnancy2003Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 92, nr 6, s. 295-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigated the influence of human pregnancy on gene expression of two cytochrome P450 enzymes in white blood cells. Cytochrome P450 1B1 (CYP1B1) catalyses oestradiol 4-hydroxylation, and may participate in the endocrine regulation of oestrogens. Cytochrome P450 2D6 (CYP2D6) metabolises many commonly used drugs, and previous studies have suggested that it is induced during pregnancy. CYP1B1 and CYP2D6 were therefore considered to be of interest in human pregnancy. As it is not ethically possible to take liver biopsies from healthy mothers during pregnancy, easily accessible cells that express the genes were used as a surrogate tissue. White blood cells were collected from eighteen pregnant women, and were used to measure CYP1B1 and CYP2D6 ribonucleic acid (RNA). The analysis was repeated after pregnancy, the women, thus, serving as their own controls. Real-time reverse transcriptase - polymerase chain reaction methods were used with 18S ribosomal RNA as an internal control. A slight, but not significant, increase in gene activity of CYP1B1 was detected during pregnancy. Expression of CYP2D6 in blood was extremely low, and induction of CYP2D6 during pregnancy could not be confirmed. In conclusion, gene expression of CYP1B1 and CYP2D6 in leukocytes was not significantly up-regulated in the third trimester of pregnancy, but a trend indicating an altered metabolism during pregnancy was detected.

  • 8. Stern, Natalia
    et al.
    Öberg, Mattias
    Casabona, Helena
    Trossvik, Christina
    Manzoor, Ellu
    Johansson, Niklas
    Lind, Monica
    Institute of Environmental Medicine, Karolinska Institutet.
    Örberg, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Feinstein, Ricardo
    Johansson, Anna
    Chu, Ih
    Poon, Raymond
    Yagminas, Al
    Brouwer, Abraham
    Jones, Bernt
    Håkansson, Helen
    Subchronic toxicity of Baltic herring oil and its fractions in the rat II: Clinical observations and toxicological parameters.2002Ingår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 91, nr 5, s. 232-244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study aimed to increase the knowledge about the toxicity of fish-derived organohalogen pollutants in mammals. The strategy chosen was to separate organohalogen pollutants derived from Baltic herring (Clupea harengus) fillet, in order to obtain fractions with differing proportions of identified and unidentified halogenated pollutants, and to perform a subchronic toxicity study in rats, essentially according to the OECD guidelines, at three dose levels. Nordic Sea lodda (Mallotus villosus) oil, with low levels of persistent organohalogen pollutants, was used as an additional control diet. The toxicological examination showed that exposure to Baltic herring oil and its fractions at dose levels corresponding to a human intake in the range of 1.6 to 34.4 kg Baltic herring per week resulted in minimal effects. The spectrum of effects was similar to that, which is observed after low-level exposure to pollutants such as chlorinated dibenzo-p-dioxins and dibenzofurans (CDD/F) and chlorinated biphenyls, despite the fact that these contaminants contribute to a minor part of the extractable organically bound chlorine (EOCl). The study confirmed previous findings that induction of hepatic ethoxyresorufin deethylase (EROD) activity takes place at daily intake levels 0.15 ng fish-derived CDD/F-TEQs/kg body weight. The study also demonstrated that hepatic vitamin A reduction takes place at somewhat higher daily exposure levels, i.e. 0.16–0.30 ng fish-derived CDD/F-TEQs/kg body weight. Halogenated fatty acids, the major component of EOCl, could not be linked to any of the measured effects. From a risk management point of view, the study provides important new information of effect levels for Ah-receptor mediated responses following low level exposure to organohalogen compounds from a matrix relevant for human exposure.

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