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  • 1
    Electronic Resource
    Electronic Resource
    Hepatic epoxide hydrase. Structure-activity relations for substrates and inhibitors (1971)
    s.l. : American Chemical Society
    Biochemistry 10 (1971), S. 4858-4866 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00802a005
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  • 2
    Electronic Resource
    Electronic Resource
    Gap junctional intercellular communication of cultured rat liver parenchymal cells is stabilized by epithelial cells and their isolated plasma membranes (1994)
    Springer
    Cellular and molecular life sciences 50 (1994), S. 124-126 
    Details
    ISSN: 1420-9071
    Keywords: Rat hepatocyte ; gap junctional intercellular communication ; coculture ; plasma membrane ; stabilization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The gap junctional intercellular communication (GJIC) determined by measuring dye coupling with Lucifer yellow, decreased within 3 d from 66% to 28% in monocultures of rat liver parenchymal cells. Coculturing of the parenchymal cells with a nonparenchymal epithelial cell line from rat liver resulted in increased and stabilized intercellular communication (83% after 3 d). The presence of isolated plasma membrane vesicles of the nonparenchymal epithelial cells also stabilized the intercellular communication between the liver parenchymal cells (70% after 3 d). When liver parenchymal cells were cocultured with a rat liver fibroblast cell line the gap junctional communication between the parenchymal cells was not stabilized (43% after 3 d), and isolated plasma membrane vesicles of the fibroblast were also unable to support the GJIC in parenchymal cells (35% after 3 d). It is concluded that plasma membrane constituents of the nonparenchymal epithelial cells were responsible for the stabilization of the GJIC between parenchymal cells. A heterotypic gap junctional communication between parenchymal and nonparenchymal cells was not observed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01984948
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  • 3
    Electronic Resource
    Electronic Resource
    The influence of dimethylbiguanide on phenprocoumon elimination and its mode of action (1983)
    Springer
    Journal of molecular medicine 61 (1983), S. 851-858 
    Details
    ISSN: 1432-1440
    Keywords: Dimethylbiguanide ; Phenprocoumon (Marcoumar) ; Enzyme induction ; Liver blood flow ; Drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study was based on the clinical observation of a higher phenprocoumon requirement in these diabetic patients simultaneously treated with phenprocoumon (MarcoumarR) and dimethylbiguanide (DMB), and of a drug interaction observed in a patient. These higher requirements of phenprocoumon, suggesting an increased elimination, could have been due to an enhancement of liver microsomal enzyme activity and/or an increase in liver blood flow. Various studies were performed to test this hypothesis. The clinically suggested higher phenprocoumon requirement was proven by a drug observation study. Hence a higher tablet consumption of phenprocoumon and a diminished anticoagulatory effect was found after treatment with DMB in doses of between 1 and 3 g. An increased elimination of phenprocoumon following DMB administration was also found in a pharmacokinetic study. The activity of the liver microsomal enzyme system, investigated in animal and man, showed no changes in the liver microsomal enzymes in animal studies or the in vivo parameters of liver microsomal enzyme activity in patients. Measuring liver blood flow in dogs, utilizing the indocyanine green clearance method, an increased flow of about 33% was observed. As changes in liver blood flow can increase the metabolism of some highly lipid soluble drugs, the increased metabolism of phenprocoumon during DMB treatment could be related to the increase in liver blood flow and not to changes in liver microsomal enzyme activity. In addition, DMB could inhibit the known enterohepatic circulation of phenprocoumon and so increase phenprocoumon elimination. Therefore, careful monitoring of the pharmacodynamic effect should be performed in those patients treated with a combination of phenprocoumon and DMB.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01537460
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  • 4
    Electronic Resource
    Electronic Resource
    Expression and inducibility of drug-metabolizing enzymes in preneoplastic and neoplastic lesions of rat liver during nitrosamine-induced hepatocarcinogenesis (1987)
    Springer
    Archives of toxicology 60 (1987), S. 198-203 
    Details
    ISSN: 1432-0738
    Keywords: Drug-metabolizing enzymes ; Liver ; Rat ; Hepatocarcinogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The expression, inducibility, and regulation of four different cytochrome (cyt.) P-450 isoenzymes (PB1, PB2, MC1, and MC2) NADPH-cytochrome P-450 reductase, the glutathione transferases (GSTs) B and C and microsomal epoxide hydrolase (mEHb) have been studied during nitrosamine-induced hepatocarcinogenesis using immunohistochemical techniques. The investigations revealed basic differences in the expression of the individual drug metabolizing enzymes in the course of neoplastic development. While the two GSTs and mEHb were increased in all preneoplastic and benign neoplastic lesions, the levels of the distinct cyt. P-450 isoenzymes were characteristically different from each other. Following initial changes in the expression of these enzymes in early preneoplastic lesions (i. e., increase of cyt. P-450 PB1 versus slight decrease of the other cyt. P-450 isoenzymes), a continuous reduction of all cyt. P-450 isoenzymes was observed during the further course of hepatocarcinogenesis. In progressed neoplastic nodules, all cyt. P-450-isoenzymes and NADPH cyt. P-450 reductase were decreased to varying extents. Treatment of animals with inducers of the monooxygenase system, such as phenobarbital, 3-methylcholanthrene and polychlorinated biphenyls, led to a rather heterogenous pattern of enzyme alterations in preneoplastic and neoplastic lesions. Following administration of phenobarbital, some islets responded to the same degree as the surrounding tissue, others were less or not at all inducible and a few of the lesions showed a prominent increase in cyt. P-450 PB2 and NADPH-cyt. P-450 reductase levels. The interesting finding that these two enzymes always showed concurrent changes may be indicative of a common regulation. Similar to phenobarbital, an induction of cyt. P-450 isoenzymes within carcinogen-induced lesions was also observed following administration of 3-methyl-cholanthrene or polychlorinated biphenyls. The results demonstrate that drug-metabolizing enzymes are abnormally regulated in carcinogen-induced lesions. The multiplicity of enzyme deviations within individual lesions and especially the enzyme inducibility strongly suggest that the focal enzyme alterations result from genotoxic effects of the carcinogen on regulatory systems of a higher order rather than from mutational events in individual structural genes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00296980
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  • 5
    Electronic Resource
    Electronic Resource
    Long-term effects of commercial and congeneric polychlorinated biphenyls on ethane production and malondialdehyde levels, indicators of in vivo lipid peroxidation (1988)
    Springer
    Archives of toxicology 62 (1988), S. 369-374 
    Details
    ISSN: 1432-0738
    Keywords: Lipid peroxidation ; Malondialdehyde ; Ethane ; Glutathione ; Polychlorinated biphenyls
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Ethane exhalation was increased in male Sprague-Dawley rats following a single intraperitoneal (IP) injection of Aroclor 1254 (500 mg/kg). In the first 2 weeks following Aroclor 1254 treatment, the increase in ethane exhalation was due to an inhibition of metabolism of endogenous ethane rather than to an increase in ethane production. In weeks 3 and 4 following Aroclor 1254 administration, metabolic clearance of ethane returned to and exceeded control levels, while ethane production increased to approximately twice the control rates (day 30). The HPLC determination of in situ hepatic malondialdehyde levels revealed a 2-fold increase in malondialdehyde content on day 30 following the Aroclor 1254 injection. Further, parallel increases in in situ malondialdehyde levels and ethane production rates were also found 30 days following a single IP injection of 3,3′,4,4′-tetrachlorobiphenyl, 2,3,4,4′,5-pentachlorobiphenyl and 2,2′,4,4′,5,5′-hexachlorobiphenyl (300 μmol/kg). These effects were not reflected in increased diene conjugation. Redox state of the liver was largely unaffected, as evidenced by the relative concentrations of reduced and oxidized NADPH. However, minor changes in reduced and oxidized glutathione were noted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293625
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  • 6
    Electronic Resource
    Electronic Resource
    Valpromide is a poor inhibitor of the cytosolic epoxide hydrolase (1989)
    Springer
    Archives of toxicology 63 (1989), S. 157-159 
    Details
    ISSN: 1432-0738
    Keywords: Cytosolic epoxide hydrolase ; Valpromide ; Liver ; Adult subjects and fetuses
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effect of the antiepileptics valpromide and sodium valproate on the cytosolic epoxide hydrolase was studied in human fetal liver, kidneys and adrenals and from human adult liver and kidneys. Trans-stilbene oxide was used as substrate. Valpromide (10 mM) lowered the activity of the epoxide hydrolase to one half of the control in all organs studied. Sodium valproate (10 mM) was less powerful as an inhibitor than valpromide; however, it exerted a significant inhibition in all tissues studied.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00316440
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  • 7
    Electronic Resource
    Electronic Resource
    Activity of O6-methylguanine DNA methyltransferase in mononuclear blood cells of formaldehyde-exposed medical students (1999)
    Springer
    Archives of toxicology 73 (1999), S. 15-21 
    Details
    ISSN: 1432-0738
    Keywords: Key words O6-methylguanine DNA methyltransferase (MGMT) ; Formaldehyde ; Mononuclear blood cells ; DNA repair
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A recent study reported that exposure of student embalmers in Cincinnati to high concentrations of formaldehyde (2 mg/m3) reduced the activity of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). Reduction in a DNA repair enzyme may strongly increase the cancer risk not only with respect to the repair-enzyme causing agent but with respect to all carcinogens causing lesions subject to repair by the enzyme in question. Thus, we examined whether formaldehyde exposure of 57 medical students during their anatomy course at two different Universities in Germany influenced MGMT activity in mononuclear blood cells. Mean formaldehyde exposure of 41 students was 0.2 ± 0.05 mg/m3 for 6 h per week. MGMT activity was 133.2 ± 14.9 fmol MGMT/106 cells before the beginning of the formaldehyde exposure, 131.1 ± 15.8 fmol MGMT/106 cells after 50 days (P = 0.56) and 128.2 ± 19.0 fmol MGMT/106 cells after 111 days of exposure (P=0.92). Similarly, no significant influence of formaldehyde exposure was observed, when smoking habits, alcohol consumption, allergic disease and sex of students were considered. In addition no significant difference was obtained in MGMT activity between 16 students with mean formaldehyde exposure of 0.8 ± 0.6 mg/m3 and students without formaldehyde exposure (n=51; P=0.37). In conclusion, exposure of the medical students in western Europe to formaldehyde did not decrease MGMT activity in mononuclear blood cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050581
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  • 8
    Electronic Resource
    Electronic Resource
    Distribution and induction of aflatoxin B1-9a-hydroxylase activity in rat liver parenchymal and non-parenchymal cells (1996)
    Springer
    Archives of toxicology 70 (1996), S. 553-558 
    Details
    ISSN: 1432-0738
    Keywords: Key words Aflatoxin B1 ; Aflatoxin B1-9a-hydroxylase ; liver ; Nonparenchymal cells ; Parenchymal cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Chronic administration of aflatoxin B1 (AFB1) to rats gives rise to hepatocellular and cholangiocellular carcinomas without affecting Kupffer and endothelial cells. The enzymatic conversion of AFB1 to AFB1-8,9-epoxide is the critical step in the activation of the mycotoxin, while the conversion of AFB1 to aflatoxin M1 (AFM1), catalyzed by the AFB1-9a-hydroxylase, is considered to be a detoxication route for the toxin. In the present study the distribution and inducibility of AFB1-9a-hydroxylase were analyzed in microsomes derived from freshly isolated liver parenchymal (PC) and nonparenchymal cells (i.e. Kupffer+endothelial cells, NPC). AFB1-9a-hydroxylase activity was clearly measurable in NPC and similar to that of PC. In NPC the rate of formation of AFM1 was higher (when incubating with 16 μM AFB1) than or similar (with 128 μM AFB1) to that of AFB1-8,9-epoxide, while in PC it was significantly lower. Taken together, these results suggest that the AFB1-9a-hydroxylase activity might be particularly important in NPC to protect these cells from AFB1 by converting it to a significantly less mutagenic metabolite and by reducing the amount of AFB1 available for epoxidation. Furthermore, it is shown that AFB1-9a-hydroxylase activity is inducible by phenobarbital (only in PC), 3-methylcholanthrene, isosafrole and Aroclor 1254, thus indicating that in rat liver the conversion of AFB1 to AFM1 is catalyzed by members of the cytochrome 1A and 2B families.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002040050312
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  • 9
    Electronic Resource
    Electronic Resource
    Significance of various enzymes in the control of reactive metabolites (1987)
    Springer
    Archives of toxicology 60 (1987), S. 174-178 
    Details
    ISSN: 1432-0738
    Keywords: Reactive metabolites ; Epoxides ; Monooxygenases ; Epoxide hydrolases ; Glutathione transferases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Most chemical carcinogens are relatively inert and need metabolic activation to the ultimately carcinogenic species. The concentration of such species is controlled by several different enzymes. Especially well studied is the important group of enzymes responsible for the control of reactive epoxides. Many natural, as well as man-made foreign compounds, including pharmaceuticals, possess olefinic or aromatic double bonds. Such compounds can be transformed to epoxides by microsomal monooxygenases present in many mammalian organs. By virtue of their electrophilic reactivity, such epoxides may spontaneously react with nucleophilic centres in the cell and thus covalently bind to DNA, RNA and protein. Such alterations of critical cellular macromolecules may disturb the normal biochemistry of the cell and lead to cytotoxic, allergic and/or carcinogenic effects. Whether such effects will be manifested depends on one hand, on the chemical reactivity as well as other properties such as geometry and lipophilicity of the epoxide in question. On the other hand, enzymes controlling the concentration of such epoxides represent a further important contributing factor: for example, several microsomal monooxygenases exist, differing in substrate specificity. With respect to large substrates, certain monooxygenases preferentially attack at a specific site different from that attacked by others. Some of these pathways lead to reactive products, whilst others are detoxification pathways. Moreover, enzymes metabolizing such epoxides represent a further determining factor. These enzymes include epoxide hydrolases and glutathione transferases. These enzymes are not solely inactivating but can also in some cases act as activating enzymes. Finally, precursor-sequestering enzymes contribute indirectly but substantially to the control of reactive metabolites. All these enzymes differ in quantity, subcellular localization and sometimes also in substrate specificity between organs, development stages, sexes and species. They therefore represent an important contributing factor to differences in susceptibilities. Further factors responsible for differences in susceptibilities include DNA repair capabilities, rate of replicative DNA synthesis and various host defense mechanisms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00296975
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  • 10
    Electronic Resource
    Electronic Resource
    Cis- and trans-1,2-diphenylaziridines: induction of xenobiotic-metabolizing enzymes in rat liver and mutagenicity in Salmonella typhimurium (1986)
    Springer
    Archives of toxicology 59 (1986), S. 242-248 
    Details
    ISSN: 1432-0738
    Keywords: cis- and trans-stilbene imine ; cis- and trans-stilbene oxide ; Acenaphthene 1,2-imine ; Drug-metabolizing enzymes ; Mutagenicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract trans-Stilbene imine (trans-1,2-diphenylaziridine) is the nitrogen analog of trans-stilbene oxide, a potent inducer of several microsomal and cytosolic xenobiotic-metabolizing enzymes. Although the acute toxicity of cis- and trans-stilbene imines prevents their application at the usual dose for trans-stilbene oxide (400 mg/kg/day), it is apparent that the imines nevertheless potently induce several xenobiotic-metabolizing enzymes in rat liver. The IP administration of trans-stilbene imine resulted in statistically significant increases in the activities of aminopyrine N-demethylase, microsomal epoxide hydrolase, glutathione transferase (toward 1-chloro-2,4-dinitrobenzene, 1,2-dichloro-4-nitrobenzene and Δ5-androstene-3,17-dione) and UDP-glucuronosyltransferase (toward testoster-one). cis-Stilbene imine was less potent in inducing these activities. Although trans-stilbene imine (total dose = 400 mg/kg) was more potent than trans-stilbene oxide (total dose = 1200 mg/kg) in inducing the activities of glutathione transferase (toward 1-chloro-2,4-dinitrobenzene) and UDP-glucuronosyltransferase (toward testosterone), both compounds belong to the class of substances which are more potent inducers of conjugating (phase II) enzymes. Because of their structural similarity with K-region arene imines which are potent mutagens, cis-stilbene imine and trans-stilbene imine were investigated for mutagenicity (reversion of his − strains of Salmonella typhimurium). cis-Stilbene imine and trans-stilbene imine were direct mutagens in the strain TA100. This result, and the finding that acenaphthene 1,2-imine efficiently reverts various strains of Salmonella typhimurium, demonstrates that not only K-region arene imines, but also other aziridines substituted at the two carbons with aromatic moieties, are mutagenic.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00290545
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