| 1. |
- Lindensjö, Bo, 1944-, et al.
(författare)
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Att utvärdera utvärdering
- 1992
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Ingår i: Forskning om utbildning. - Stockholm : Symposion Brutus Östlings bokförlag. - 9171390928
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 2. |
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| 3. |
- Lundgren, Bo, et al.
(författare)
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The metabolism of xenobiotics and its relationship to toxicity/genotoxicity : studies with human lymphocytes.
- 1990
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Ingår i: Acta Physiologica Scandinavica Supplementum. - 0302-2994. ; 592
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Tidskriftsartikel (refereegranskat)abstract
- Most compounds considered to be foreign to the human body are rather hydrophobic and chemically inert. Because of their hydrophobicity, xenobiotics enter the body easily by diffusion through biological membranes, are difficult to excrete in unchanged form in the urine and bile and accumulate in hydrophobic compartments of the cell, including the phospholipid bilayer of membranes, where they can disturb normal cellular functions. In order to transform xenobiotics into products which are more readily excretable, enzymes of detoxication first activate these substances (primarily via the cytochrome P-450 monooxygenase system) to intermediates which are often highly electrophilic and reactive, such as epoxides, free radicals and carbonium ions. These intermediates are then partially inactivated and their solubility in water simultaneously increased through the addition of water (by epoxide hydrolases) or conjugation with glutathione (by glutathione transferases). Finally, an additional increase in water solubility can be achieved by conjugation with, for example, sulfate (via sulfotransferases) and/or glucuronic acid (via UDP-glucuronyltransferases). Unfortunately, reactive intermediates of xenobiotic metabolism which are not inactivated sufficiently rapidly can bind covalently to many nucleophilic groups in the cell, including those on DNA, RNA and protein. Most often, because of various cellular defense mechanisms, such binding causes no serious damage. However, in some cases toxic and/or genotoxic effects may be produced. As an alternative to experimentation with animals, we have examined xenobiotic metabolism in circulating mononuclear leukocytes from human beings. Certain enzymes of detoxication--including membrane-bound and cytosolic epoxide hydrolases and cytosolic glutathione transferases--can be easily measured and characterized in preparations from these cells. Autosomal dominant hereditary differences of at least several hundred-fold in the activity of glutathione transferase mu in circulating human lymphocytes were observed, differences which may be of value in predicting an individual's risk for toxic/genotoxic damage after exposure to certain xenobiotics.
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| 4. |
- Lundgren, Bo
(författare)
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Trafiksäkerhetsprogram
- 1991
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Ingår i: VTI:s och TFB:s forskardagar. - Linköping : Statens väg- och transportforskningsinstitut. ; , s. 33-43
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 5. |
- Lundgren, Johan, et al.
(författare)
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Acidosis-induced ischemic brain damage: are free radicals involved?
- 1991
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - 1559-7016. ; 11:4, s. 587-596
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Tidskriftsartikel (refereegranskat)abstract
- Substantial evidence exists that reactive oxygen species participate in the pathogenesis of brain damage following both sustained and transient cerebral ischemia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely triggering event for free radical damage is delocalization of protein-bound iron. The binding capacity for some iron-binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of H2O2, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and substantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cerebrospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (GSH + GSSH) in cortex and hippocampus, and levels of alpha-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H2O2 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce increased H2O2 production. No difference in free iron in CSF was observed between animals subjected to ischemia under hyper- and normoglycemic conditions. The moderate decrease in total glutathione or alpha-tocopherol levels did not differ between normo- and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular compartment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.
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| 6. |
- Olsson, U, et al.
(författare)
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Effects of selenium deficiency on xenobiotic-metabolizing and other enzymes in rat liver.
- 1993
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Ingår i: International Journal for Vitamin and Nutrition Research. - 0300-9831 .- 1664-2821. ; 63:1
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Tidskriftsartikel (refereegranskat)abstract
- The present study was undertaken to characterize effects of selenium (Se) deficiency on 16 enzymes recovered in either one or more of the subcellular fractions of rat liver (as a basis for future studies on the mechanisms underlying the observed changes). Male rats were fed a Torula-yeast based diet with 0.23 mg Se/kg or the same diet with 0.009 mg Se/kg, from weaning and for 10 weeks. Statistically significant effects of Se deficiency were the following: Se-dependent glutathione peroxidase decreased to 0.14% of the Se-adequate controls, while cytosolic glutathione transferase increased 3-fold in Se deficiency when CDNB was the substrate, but decreased significantly when trans-stilbene oxide (diagnostic for subunit 4) was used as the substrate. Cytosolic DT-diaphorase increased about 7-fold in Se deficiency. Further, DT-diaphorase in the microsomal fraction was also significantly increased in Se deficiency, as were the microsomal and mitochondrial epoxide hydrolases and microsomal glutathione transferase. Furthermore, increased activity of the peroxisomal marker enzyme catalase (P < 0.05) was noted in Se-deficient rats. It is our working hypothesis that changes in enzyme activities in Se deficiency are mainly due to changed levels of endogenously generated metabolites or altered functions of endocrine tissues.
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| 7. |
- Olsson, U, et al.
(författare)
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The involvement of selenium in peroxisome proliferation caused by dietary administration of clofibrate to rats.
- 1992
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Ingår i: Chemico-Biological Interactions. - 0009-2797 .- 1872-7786. ; 85:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Permadi, H, et al.
(författare)
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Effects of perfluoro fatty acids on peroxisome proliferation and mitochondrial size in mouse liver : dose and time factors and effect of chain length.
- 1993
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Ingår i: Xenobiotica. - 0049-8254 .- 1366-5928. ; 23:7
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Tidskriftsartikel (refereegranskat)abstract
- 1. Male mice were fed a diet containing perfluoro fatty acids of varying chain length (i.e. perfluoroacetic, -butyric, -octanoic and -decanoic acids) at different doses (0.02 or 0.1% w/w of diet) for different periods of time (2-10 days), and effects on liver weight, hepatic mitochondrial protein and hepatic peroxisomal palmitoyl-CoA oxidation, lauroyl-CoA oxidase and catalase were monitored. 2. The greatest effects were obtained with perfluoro-octanoic and perfluoro decanoic acids, while perfluoro acetic acid was inactive. The effects with 0.02% w/w of diet perfluoro-octanoic acid were at least as great as those observed with 0.1%. A more detailed dose-response investigation focused on perfluoro-octanoic acid revealed that maximal effects with this substance could be obtained with a dietary dose of 0.01% for 10 days and that significant changes were also observed with 0.001%. 3. Maximal effects with 0.02% w/w of diet perfluoro-octanoic acid were attained after 6-10 days of feeding. 4. As with other peroxisome proliferators, perfluoro fatty acids increase mouse hepatic peroxisomal fatty acid beta-oxidation more extensively than they increase catalase, thus increasing hepatic oxidative stress. 5. As with other peroxisome proliferators, perfluoro fatty acids increase mouse liver mitochondrial protein. This effect is due primarily to a redistribution of mitochondria from the nuclear to the mitochondrial fraction, caused by an apparent decrease in the mean size of hepatic mitochondria after treatment.
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| 9. |
- Sundberg, C, et al.
(författare)
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Comparison of the potencies of (+)- and (-)-2-ethylhexanoic acid in causing peroxisome proliferation and related biological effects in mouse liver.
- 1994
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Ingår i: Chirality. - : Wiley. - 0899-0042 .- 1520-636X. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Male C57BL/6 mice were exposed to 1% (w/w) (+)- or (-)-2-ethylhexanoic acid or an equimolar mixture of these enantiomers in their diet for 4 or 10 days. A significant increase in liver weight and a 2- to 3-fold increase in the protein content of the mitochondrial fraction were seen in all cases. Peroxisomal palmitoyl-CoA oxidation was increased 2- to 3.5-fold after 4 days of treatment and 4- to 5-fold after 10 days, while the corresponding increases in peroxisomal lauroyl-CoA oxidase activity were 2- to 3-fold and 9- to 12-fold, respectively. Peroxisomal catalase activity was unchanged, whereas the microsomal and cytosolic activities were increased 2- to 3-fold and 6- to 16-fold, respectively. These treatments also induced microsomal omega-hydroxylation of lauric acid 7-fold and soluble epoxide hydrolase activity in the mitochondrial and cytosolic fractions, as well as microsomal epoxide hydrolase activity about 50-100%. The only significant differences observed between the effects of (+)-2-ethylhexanoic acid and its (-)-enantiomer were on peroxisomal palmitoyl-CoA oxidation and lauroyl-CoA oxidase activity after 4 days of treatment. In both these cases the (+)-enantiomer resulted in increases which were 50-75% greater than those seen with the (-)-form.
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| 10. |
- Wormald, P, et al.
(författare)
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Interaction of phospholipids with rhodamine 6G in toluene.
- 1992
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Ingår i: Acta Chemica Scandinavica. - 0904-213X .- 1902-3103. ; 46:1
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Tidskriftsartikel (refereegranskat)abstract
- Upon interaction of various glycerophospholipids with Rhodamine 6G in toluene, a typical difference spectrum with an absorption maximum at approximately 515 nm is obtained . This spectrum is obtained with phosphatidylcholine only after treatment with NaCl, which presumably weakens intra- and/or inter-molecular electrostatic binding between the negatively charged phosphate moiety and the protonated nitrogen in this molecule. Absorption at 515 nm was linear for all of the phospholipids investigated from a concentration of approximately 1.2 microM up to at least 50 microM. The highest extinction coefficient was obtained for diphosphatidylglycerol (251 mM-1 cm-1) and all of the compounds tested, with the exception of phosphatidylethanolamine, demonstrated extinction coefficients higher than that of palmitic acid. Thus, the absorption spectrum which results from the interaction of purified glycerophospholipids with Rhodamine 6G in organic solvent is a sensitive measure of the amount of phospholipid present.
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