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Biomedical subjects

F Oesch

Publications and source records attributed to F Oesch.

At least 397 records · Page 22Linked to original sources
PubMed1980

Interindividual comparison of epoxide hydratase and glutathione S-transferase activities in cultured human fibroblasts.

Epoxide hydratase activity with benzo[a]pyrene 4,5-oxide and glutathione S-transferase activity with 2,4-dinitrochlorobenzene as substrates were determined in cultured fibroblasts from skin biopsies of different donors and from several biopsies of the same donor. Variation of the results from experiment to experiment was reduced by the use of a reference cell strain and expression of the results as activities relative to those of the reference cells. Epoxide hydratase activity varied 2.3-fold in 39 cultures from the same subject (the variation coefficients were 0.22 and 0.15, respectively). The results indicate that, at least in skin fibroblasts, genetically caused interindividual differences in epoxide hydratase activities do not exist or are negligibly small or very rare. Glutathione S-transferase activity varied more in cultures from different donors (variation coefficient = 0.22) than in different cultures from the same donor (variation coefficient = 0.08), but the highest and the lowest activities only differed by a factor of 2.3. No significant differences in either enzyme activity were observed between males, females, subjects without tumours, lung carcinoma bearers and melanoma patients.

Adult↗
PubMed1980

Distribution of enzymes involved in metabolism of polycyclic aromatic hydrocarbons among rat liver endomembranes and plasma membranes.

The distribution of membrane-bound enzymes involved in the metabolism of polycyclic aromatic hydrocarbons was investigated in the same animals, in membrane fractions from rat liver: monooxygenase, cytochromes P-450 and P-420, NADPH-cytochrome P-450 reductase, cytochrome b5, NADH-cytochrome b5 reductase, epoxide hydrolase, glutathione-S-transferase, and UDP-glucuronyltransferase. The purity of the fractions (rough and smooth endoplasmic reticulum (ER), nuclei, nuclear membranes, Golgi apparatus, plasma membranes, and mitochondria) was controlled by electron microscopic morphometry, chemical analysis, and determination of marker enzyme activities. Specific activities invariably were highest in ER. With respect to the distribution between smooth and rough ER, the enzymes fell into two groups: Epoxide hydrolase, monooxygenase, NADPH-cytochrome P-450 reductase, NADH-cytochrome b5 reductase, and the concentrations of cytochromes P-450 and b5 were higher in smooth ER; by contrast, UDP-glucuronyltransferase (maximally activated) and membrane-associated glutathione-S-transferase activities were lower in smooth ER. The non-ER fractions also had significant activities of the enzymes, but to different extents: (1) Nuclei and nuclear membranes showed high UDP-glucuronyltransferase activities (on a phospholipid basis 55-65% of that of rough ER) which did not exhibit latency. (2) Plasma membrane, Golgi apparatus, and nuclear membrane fractions had relatively high epoxide hydrolase and NADH-cytochrome b5 reductase activities as well as high concentrations of cytochromes b5 and P-450 (20-30% of levels present in smooth ER on a phospholipid basis). (3) In mitochondria (whole organelles), glutathione-S-transferase. UDP-glucuronyltransferase, and NADH-cytochrome b5 reductase activities were high, in contrast to exceedingly low (or absent) amounts of cytochrome P-450 and activities of cytochrome P-450 reductase, monooxygenase, and epoxide hydrolase. The data show that (i) aromatic hydrocarbons are metabolized not only in ER membranes but also in other kinds of membranes, including Golgi apparatus and plasma membrane, and (ii) the mode and extent of this metabolism can differ in different membranes. Such differences of activities of enzymes present in the specific membranes might lead to differences of the intracellular distribution of reactive and inactive metabolites of aromatic hydrocarbons and thus may be important in diversification and regulation of metabolic pathways of carcinogenic compounds.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1980

Epoxide hydrolase activity in native and in mitogen-stimulated lymphocytes of various human donors.

An assay for epoxide hydrolase activity using benzo(a)-pyrene 4,5-oxide as substrate was modified in such a manner that it allowed the estimation of activities in native and in cultivated mitogen-stimulated human lymphocytes. Their specific activities were about 1000-fold lower than those of human or rat liver microsomes. In native lymphocytes of 28 subjects, the specific activities of epoxide hydrolase varied from 2.0 to 7.2 pmol/min/mg protein. Repeated measurements in the same subjects usually showed reasonable consistency of the activity (variation less than 1.8-fold), but in 3 of 12 subjects the activity varied between 2.5- and 3-fold. This indicates that epigenetic factors can alter the activity. To circumvent effects due to variable exposure to such modulating factors, lymphocytes were cultivated and stimulated by mitogens. In such cells, the variation of enzyme activity clearly decreased. The specific activities in stimulated lymphocytes from 12 donors varied only from 4.4 to 7.0 pmol/min/mg protein. Phenobarbital, pregnenolone-16 alpha-carbonitrile, trans-stilbene oxide, 3-methylcholanthrene, and benzo(a)anthracene in the culture medium did not significantly induce or activate epoxide hydrolase, but beta-naphthoflavone increased the activity. The effect was similar in lymphocytes of 13 different donors, the highest and lowest increases being 1.8- and 2.6-fold. Thus, no genetic heterogeneity of epoxide hydrolase was observed in native or in cultivated and stimulated lymphocytes or in the response to beta-naphthoflavone. Between males and females or smokers and nonsmokers, no significant differences occurred. Inter- and intraindividual variation of epoxide hydrolase activity in native lymphocytes appears to be due almost exclusively to epigenetic factors, e.g., composition of the lymphocyte population or in vivo exposure to unknown modulators of epoxide hydrolase.

Adult↗
PubMed1979

Metabolites of diethylstilboestrol induce sister chromatid exchange in human cultured fibroblasts.

Diethylstilboesterol (DES) is one of the few substances for which a clear association with carcinogenicity has been established in man. Nevertheless, it is still widely used, mainly as a cheap oestrogen to increase the slaughter weight of beef, but in spite of this it is not known if residues in the meat or metabolites excreted by the cattle are hazardous to man. It is also unknown whether there is a threshold dose below which DES is harmless. A threshold might be expected if a hormonal mechanism of carcinogensis rather than metabolic activation to an electrophically reactive species operats. This possibility was supported by the observations that DES, in contrast to most other carcinogens, failed to induce mutations in the Salmonella/microsome test or malignant transformations of eukaryotic cells in culture. It is also disturbing that DES, one of the few known human carcinogens was negative in these two most widely used short-term tests introduced as fast early-earning system for potential carcinogens. We now report that DES is positive in sister chromatid exchange (SCE) induction, a short-term test for which a high correlation with the carcinogenicity of the compounds tested has been observed. Moreover, we show that metabolic activation was involved. Two different pathways leading to metabolites much more active in SCE induction than DES itself ('proximate agents') were established.

Cells, Cultured↗
PubMed1979

Mutagenicity of 43 structurally related heterocyclic compounds and its relationship to their carcinogenicity.

43 heteropolycyclic compounds belonging to a homologous series were investigated for mutagenicity. The results are compared with carcinogenicity data obtained with the same batches of compounds under conditions identical for all of them. Mutagenicity was tested in the Ames test with Salmonella typhimurium strains TA1535, TA1537 and TA100 in the presence and absence of liver 10 000 g supernatant from rats treated with Aroclor 1254. Carcinogenicity was tested by injection of the compounds into subcutaneous tissue of XVIInc/Z mice. 18 test compounds showed carcinogenic activity, some strongly, others only weakly. Of these, 17 were detected as mutagens: one weak carcinogen did not revert the Salmonella strains. No quantitative correlation was observed between the extents of the mutagenic and the carcinogenic effects. Of the 25 substances that did not produce tumours, 13 showed mutagenicity (12 in the presence, 2 in the absence, of the liver homogenate). The mutagenic effects of these compounds were quantitatively similar to those of the compounds that produced tumours. The most sensitive strain of Salmonella typhimurium was TA100. It detected all 30 mutagens. TA98 was mutated by 25 compounds, TA1537 by 16 compounds. No mutagenic effects were seen with TA1535. Possible reasons for the high percentage of apparently "false positives" in the Ames test and the lack of a quantitative correlation between the potency of the mutagenic and carcinogenic effects are discussed. It is suggested that the complexity of the metabolism of these heterocyclic compounds may lead to critical differences in metabolism in mouse subcutaneous tissue in vivo and in liver homogenates from rats treated with Aroclor. Therefore the present study will be extended to life-long oral and intrahepatic carcinogenicity tests leading to a higher proportion of metabolism in the liver.

Carcinogens↗
PubMed1979

delta 1-Tetrahydrocannabinol and 1 alpha, 2 alpha-epoxyhexahydrocannabinol: mutagenicity investigation in the Ames test.

1,2-Epoxyhexahydrocannabinol is a metabolite of delta 1-tetrahydrocannabinol. Because many epoxides are mutagens, we investigated 1,2-epoxyhexahydrocannabinol as well as delta 1-tetrahydrocannabinol for mutagenicity with Salmonella typhimurium TA1535, TA1537, TA98 and TA100 in the presence and in the absence of S9 mix from liver homogenate of rats treated with Aroclor 1254. Additionally, an epoxide hydratase inhibitor was used in some experiments. Whereas several other epoxides and further positive controls, not requiring activation or activated under the same conditions, respectively, showed strong mutagenicity, no indications of a mutagenic hazard by 1,2-epoxyhexahydrocannabinol or by delta 1-tetrahydrocannabinol were found.

Dronabinol↗