Search Results - (Author, Cooperation:D. Schrenk)

2011-10-07

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Autocrine Communication ; Brain Neoplasms/genetics/immunology/*metabolism/*pathology ; Cell Line, Tumor ; Cell Survival ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Glioma/genetics/immunology/*metabolism/*pathology ; Humans ; Kynurenine/immunology/*metabolism/pharmacology/secretion ; Ligands ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; Paracrine Communication ; Receptors, Aryl Hydrocarbon/immunology/*metabolism ; Tryptophan/metabolism ; Tryptophan Oxygenase/deficiency/genetics/metabolism

1432-1041

Smoking ; Omeprazole ; Cytochrome P4501A ; UDP-glucuronosyltransferase ; duodenal biopsies

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Abstract Drug-metabolizing enzymes were investigated in duodenal biopsy specimens. Cytochrome P4501A (CYP1A) activity was determined by measuring 7-ethoxyresorufin O-deethylase (EROD) activity in biopsies from 20 smokers (3–30 cigarettes per day), 21 nonsmokers, and 10 nonsmokers receiving omeprazole treatment (20–60 mg/day for at least 1 week). Omeprazole is known to act as a polycyclic aromatic hydrocarbon (PAH)-type inducer in humans. EROD activity was found to be significantly induced in smokers and omeprazole-treated patients, with medians of 2.1 and 1.1 pmol· min−1·mg protein−1, respectively, compared with 0.5 pmol·min−1·mg protein−1 in nonsmokers. Immunoblot analysis substantiated that EROD activity was correlated with CYP1A protein. In contrast, UDP-glucuronosyltransferase (UGT) activity towards 4-methylumbelliferone (an overlapping substrate of several constitutive and inducible UGTs) was not significantly affected. The results demonstrate CYP1A induction by omeprazole and by constituents of cigarette smoke in the human duodenum and support the utility of duodenal biopsies to monitor CYP1A induction by PAH-type inducers.

Electronic Resource

1432-1041

Key words Caffeine metabolism ; Cigarette smokers

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Abstract Objective: To analyse distributions of a urinary ratio of caffeine metabolites (MRc) representative of cytochrome P450 (CYP) 1A2 activity in a cohort of Caucasian German healthy volunteers and to re-assess the effects of smoking and oral contraceptives on the range and type of MRc distribution. Methods: A cohort of volunteers comprising 192 individuals (96 males, 96 females) was divided into subgroups according to smoking and/or use of oral contraceptives. The CYP1A2 substrate caffeine was administered, and urine was collected for 6 h and analysed for representative caffeine metabolites. Distribution of a CYP1A2-dependent MRc was analysed using cumulative distribution (probit) plots and Rosin-Rammler-Sperling-Weibull (RRSW) functions. Results: Cumulative distribution curves for males, and females, without further subgrouping for smoking habits and/or oral contraceptive steroid (OCS) consumption, showed slightly higher MRc values, i.e. slightly higher CYP1A2 activities, in males. Significantly higher MRc values were found in smokers of both sexes than in non-smokers. The distributions among female non-smokers or smokers with and without OCS were nearly superimposible, however. For the two male subgroups, the sum of two RRSW functions resulted in a better adjustment to the data than a unimodal skewed distribution. A weak correlation between MRc and the number of cigarettes smoked per day was found. Conclusion: The inducing effect of smoking on CYP1A2 activity was confirmed, whereas no significant inhibitory effect of oral contraceptives was observed. The finding that the data are compatible with bimodal distributions in non-smokers suggests a significant impact of genetic factors on MRc. Among smokers, data were also compatible with bimodal distributions, i.e. with the existence of a “non-responder” phenotype concerning CYP1A2 induction by compounds present in tobacco smoke.

Electronic Resource

1432-1335

Dimethylnitrosamin ; Cytochrom P-450 ; Äthanol ; Leber ; Dimethylnitrosamine ; Cytochrome P-450 ; Ethanol ; Liver

Springer Online Journal Archives 1860-2000

Medicine

Summary Rat liver microsomes were prepared from male and female controls and from animals pretreated for 3 weeks with ethanol, and incubated with dimethylnitrosamine (DMN) and an NADPH-regenerating system. The formation of formaldehyde and nitrite as well as the alkylation of microsomal protein were found to be greatly enhanced, especially in the low DMN concentration range, as a result of long-term ethanol induction. In contrast, ethanol or tetrahydrofuran, when incubated simultaneously with DMN, inhibited microsomal metabolism of the carcinogen.

Zusammenfassung Von unbehandelten oder für 3 Wochen mit Äthanol vorbehandelten männlichen und weiblichen Ratten wurden Lebermikrosomen isoliert und mit dimethylnitrosamin (DMN) und einem NADPH regenerierenden System inkubiert. Die Vorbehandlung mit Äthanol führte zu einer starken Steigerung der Formaldehyd- und Nitritbildung sowie der Alkylierung mikrosomaler Proteine speziell im niedrigen DMN Dosisbereich. Im Gegensatz hierzu wurde bei in vitro Zugabe von Äthanol oder Tetrahydrofuran der mikrosomale metabolismus von DMN gehemmt.

Electronic Resource

1573-6822

drug metabolism ; drug resistance ; hepatocarcinogenesis ; oval cells ; parenchymal cells

Springer Online Journal Archives 1860-2000

Biology

Medicine

Abstract The activities of several different phase I and phase II drug-metabolizing enzymes were measured in freshly isolated oval cells from rats fed a choline-deficient/DL-ethionine-supplemented diet for 6 weeks and alsoin vitro in the established oval cell line OC/CDE 6. No cytochrome P450 was spectrophotometrically measurable in both preparations and two cytochrome P450-dependent monoxygenase activities, aminopyrineN-demethylase and ethoxyresorufinO-deethylase, could not be detected in the oval cells of both sources. However, cytosolic glutathione transferase, microsomal expoxide hydrolase and UDP-glucuronosyltransferase activities were clearly measurable in oval cells. Similar enzyme activities were found in freshly isolated and cultured oval cells. The highest activities of these three enzymes were detected during the exponential growth phase of the cultured cells; thereafter the activities decreased until the cells reached confluency. Changes in phenol UDP-glucuronosyltransferase (UGT1A1) mRNA levels paralleled the variations in UDP-glucuronosyltransferase activity, i.e. they were high in exponentially growing oval cells and low in confluent cell cultures. Taking into account that oval cells are able to proliferate in the livers of rats continuously fed a choline-deficient/DL-ethionine-supplemented diet and that none of the analyzed drug metabolizing enzymes are involved in the activation or detoxication ofDL-ethionine, the described pattern might be part of a more general, nonspecific, protection mechanism enabling these cells to overcome the cytotoxic effects of a variety of carcinogens and to proliferate even in their presence. Furthermore, the expression of microsomal epoxide hydrolase, cytosolic glutathione transferase and UDP-glucuronosyltransferase appears to depend on the proliferative status of the cells.

Electronic Resource