1. A primary cell culture from rainbow trout (Oncorhynchus mykiss) liver was prepared and evaluated for biotransformation of xenobiotics. 2. The hepatocytes maintained cytochrome P-450 content, as well as their cytochrome P-450-dependent activities, stable for 5-6 days in serum-free medium. Protein and glutathione levels, as well as other enzyme activities important for biotransformation, were close to their fresh cell levels throughout the culture period. 3. The cells were also responsive to cytochrome P-450 inducers. Both beta-naphthoflavone (BNF) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) caused an increase in ethoxyresorufin O-deethylase (EROD) activity, which was dose-dependent over the concentration ranges of 3.6-360 nM and 2.5-100 pM, respectively. The induced activities in BNF-exposed cells returned to basal levels within 48 h after replacing the medium with a BNF-free medium. Exposure of cells to TCDD (100 pM) for 48 h induced EROD activity which, in contrast to response of BNF-exposed cells, continued to increase after the medium had been replaced with TCDD-free medium. 4. The results show that trout hepatocytes in primary culture afford a reliable in vitro method for studying the regulation and functions of xenobiotic biotransformation enzymes, and for defining toxic effects of aquatic pollutants in cells.

Using nozzle beams of He, Ne, and Ar, we have measured diffractive selective adsorption resonances from a Cu(110) surface kept at 20 K. Bound state energies of the atom-surface potentials have been determined from plots of the measured resonance energies versus incident angle and their fits to calculated kinematical dispersion relations. For 3He and 4He we have found a unique level assignment that is compatible with a single gas-surface potential curve with a well depth of 6.05 meV of the He-Cu(110) potential. This value is about 10% larger than the prediction of 5.55 meV from the current physisorption theory. The Ne and Ar data reveal a large number of closely spaced levels with level separations and estimated van der Waals coefficients that are compatible with available theoretical data.

Aim: To determine the pharmacokinetics (PK) of esomeprazole after single and repeated oral doses in adolescent patients (age, 12-17 years inclusive) with gastroesophageal reflux disease (GERD) symptoms. Methods: In this single-center, randomized, open-label study (D961400094), 28 adolescents (13 girls) received esomeprazole 20-or 40-mg capsules once daily for 8 days. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4 and 6 hours post dose on days 1 and 8. Normal-phase liquid chromatography and ultraviolet detection (limit of quantification, 0.025 μmol/L) were used to determine plasma esomeprazole concentrations. PK parameters were calculated by a noncompartmental approach using WINNONLIN software. Results: The PK parameters of these adolescents and published values (Physician's Desk Reference Electronic Library [pdrel.thomsonhc.com]) of adults with suspected or established GERD are shown below. Summary: Esomeprazole seems to have both dose-and time-dependent PK changes in these patients. A doubled dose results in more than a doubled overall exposure (AUC) and Cmax for both single and repeated doses. The T½ was also approximately 50% longer for the higher or repeated dose compared with the lower or single dose. The PK parameters in adolescents are generally comparable with those observed in adults. The few observed adverse events were of mild intensity. Conclusion: The PK profile of esomeprazole in adolescent patients with symptoms of GERD is similar to that in adults.Table

Slow heavy atoms scattering from cold surfaces excite many phonons, but still have a finite elastic scattering fraction. We have measured the coherent elastic intensity of low-energy Ne, Ar, and Kr beams scattered from a Cu(111) surface, and compared the results to accurate semiclassical calculations. Earlier experiments have been extended to a range of incident beam energies, while earlier calculations have been improved by using state-of-the-art atom-surface potentials and surface phonon densities of states. All inputs to the calculations are taken from the literature. so they involve no adjustable parameters. We compare both the zero-temperature limit and the thermal attenuation of the elastic scattering at elevated temperatures. Our comparisons confirm that the probability for elastic scattering is (i) independent of particle mass in at low surface temperatures and (ii) depends on rootm at elevated temperatures, Corresponding experimental observations for the comparatively light, Particles H-2, D-2 and He show clear deviations from the semiclassical predictions. Our analysis, shows that this regime provides new and complementary information about both surface phonons and atom-surface potentials.

We report observations of coherent elastic and rotationally inelastic scattering of N2, O2, and CH4 from a 10 K Cu(111) surface, kept clean by pulsed laser heating. The related sharp features in the measured angular distributions decrease drastically in intensity at elevated target temperatures. At low temperature rotational transitions reduce the elastic scattering probability by about an order of magnitude. This effect is weak for D2 at the impact conditions of concern. Quantum scattering calculations for N2 and D2 show that this difference is primarily caused by the large difference in rotational constants and the associated rotational transition energies of these molecules.

Introduction: 0 is mainly metabolized by cytochrome P450 (CYP) 2C19, which forms hydroxyomeprazole.The sulphone is formed by CYP3A4.0 is administered as a racemic mixture of its 2 optical isomers, E and R-O.The aim of this study was to investigate whether the metabolism of the optical isomers is different from each other.Methods: Samples from 3 livers were used for human liver microsomal studies, and 4 healthy males were used for in vivo PK and PD studies.The subjects were given 0, E, or R-O, 15 mg qd over 7 days, in a randomized, 3-way crossover design.The PK was studied on days I and 7. PAO was measured on days 0 and 7. Results: In vitro studies demonstrated that E was less hydroxylated (CYP2CI9 mediated reaction) than R-O and that the total intrinsic clearance for E was lower than for R-O.The in vivo studies demonstrated that the mean AUC on day 7 was almost 2x greater for E and approximately 0.5x for R-O, both as compared with 0 (Figure).This resulted in a more pronounced effect on PAO for E than for 0 and R-O (91% vs 65 and 25% inhibition, resp.)Conclusion: The almost 2-fold higher AUC for E than for 5550

A Reply to the Comment by A. Siber and B. Gumhalter.Received 10 March 1998DOI:https://doi.org/10.1103/PhysRevLett.81.1743©1998 American Physical Society

The purpose of the study was to evaluate the hepatic 7-ethoxyresorufin O-deethylase (ERO D)-induction and whole fry immunohistochemical staining of cytochrome P4501A1 in two different salmonid species exposed by microinjection to the lipid soluble components extracted from feral Baltic salmon (Salmo salar) roe predicted to develop the larval mortality syndrome M74. In both salmon and brown trout (Salmo trutta), a dose-dependent induction of the hepatic EROD-activity was recorded. No dose-dependent induction was seen in groups exposed to different concentrations of the lipophilic substances extracted from farmed roe. The immunohistochemical study revealed an exposure-dependent induction of cytochrome P4501A1 in the liver and in endothelial tissue in both salmon and brown trout.

This review updates and evaluates the currently available information regarding the pharmacokinetics, metabolism and interactions of the acid pump inhibitors omeprazole, lansoprazole and pantoprazole. Differences and similarities between the compounds are discussed.Omeprazole, lansoprazole and pantoprazole are all mainly metabolised by the polymorphically expressed cytochrome P450 (CYP) isoform S-mephenytoin hydroxylase (CYP2C19), which means that within a population a few individuals (3% of Caucasians) metabolise the compounds slowly compared with the majority of the population. For all 3 compounds, the area under the plasma concentration-versus-time curve (AUG) for a slow metaboliser is, in general, approximately 5 times higher than that in an average patient, Since all 3 compounds are considered safe and well tolerated, and no dosage-related adverse drug reactions have been identified, this finding seems to be of no clinical relevance.The acid pump inhibitors seem to be similarly handled in the elderly, where a somewhat slower elimination can be demonstrated compared with young individuals. In patients with renal insufficiency, omeprazole is eliminated as in healthy individuals, whereas the data on lansoprazole and pantoprazole are unresolved. In patients with hepatic insufficiency, as expected, the elimination rates of all 3 compounds are substantially decreased.No clinically relevant effects on specific endogenous glandular functions, such as the adrenal (cortisol), the gonads or the thyroid, were demonstrated for omeprazole and pantoprazole, whereas a few minor concerns have been raised regarding lansoprazole.The absorption of some compounds, e.g. digoxin, might be altered as a result of the increased gastric pH obtained during treatment with acid pump inhibitors, and, accordingly, similar effects are expected irrespective of which acid pump inhibitor is given.The effect of the acid pump inhibitors on enzymes in the liver has been intensely debated, and some authors have claimed that lansoprazole and pantoprazole have less potential than omeprazole to interact with other drugs metabolised by CYP. However, after assessment of available data in this area, the conclusion is Chat all 3 acid pump inhibitors have a very limited potential for drug interactions at the CYP level. In addition, the small effects on CYP reported for these compounds are rarely of any clinical relevance, considering the normal intra- (and inter-)individual variations in metabolism observed for most drugs.In conclusion, omeprazole, lansoprazole and pantoprazole are structurally very similar, and an evaluation of available data indicates that also with respect to pharmacokinetics, metabolism and interactions in general they demonstrate very similar properties, even though omeprazole has been mon thoroughly studied with regard to different effects.

This study focused on investigation of the accumulation and distribution of mercury (Hg) in mushrooms of the genus Leccinum that emerged on soils of totally different geochemical bedrock composition. Hg in 6 species from geographically diverse regions of the mercuriferous belt areas in Yunnan of SW China, and 8 species from the non-mercuriferous regions of Poland in Europe was measured. Also assessed was the probable dietary intake of Hg from consumption of Leccinum spp., which are traditional organic food items in SW China and Poland. The results showed that L. chromapes, L. extremiorientale, L. griseum and L. rugosicepes are good accumulators of Hg and the sequestered Hg in caps were up to 4.8, 3.5, 3.6 and 4.7 mg Hg kg− 1 dry matter respectively. Leccinum mushrooms from Poland also efficiently accumulated Hg with their average Hg content being an order of magnitude lower due to low concentrations of Hg in forest topsoil of Poland compared to the elevated contents in Yunnan. Consumption of Leccinum mushrooms with elevated Hg contents in Yunnan at rates of up to 300 g fresh product per week during the foraging season would not result in Hg intake that exceeds the provisional weekly tolerance limit of 0.004 mg kg− 1 body mass, assuming no Hg ingestion from other foods.

The studies were performed on perch (Perca fluviatilis) caught outside Husum and Iggesund kraft pulp mills in 1985 and 1987, respectively, and the results were compared to previous observations from 1984 to 1985 in the receiving waters of the Norrsundet kraft pulp mill. The studies revealed that the biochemical and physiological variables, i.e., EROD activity, gonad size, number of lymphocytes, carbohydrate metabolites, and plasma ion composition, can be used as sensitive and reliable indicators of toxic effects on natural populations of fish exposed to conventional chlorine-bleached kraft mill effluents. However; the effects were generally less pronounced and indicated less geographic extension than those seen in perch previously investigated in the receiving waters of the Norrsundet kraft pulp mill. Based on these studies on perch at Husum and Iggesund and the previous studies at Norrsundet it can be concluded that the chlorine-bleached kraft mill effluents cause serious disturbances to vital biochemical and physiological functions, which can affect the health status and presumably also the survival of the fish. Finally, the responses do not reflect the present situation in the receiving waters since all three mills have taken extensive measures for process alterations and discharge reductions after the time of the investigations.

1. The activation of proguanil to cycloguanil by human liver microsomes was studied to define the cytochrome P450 (CYP) isoforms involved in this reaction. 2. Apparent Km values for proguanil ranged from 35 microM to 183 microM with microsomes from four human livers. 3. There was a 6.3-fold range of activity with microsomes from seventeen human livers. Rates of proguanil activation correlated significantly with CYP3A activities (benzo[a]pyrene metabolism, caffeine 8-oxidation and omeprazole sulphone formation) and CYP3A immunoreactive content. There was also a highly significant correlation with rates of hydroxyomeprazole formation. Correlations with activities selective for CYP1A2, CYP2C9/10 and CYP2E1, and with immunoreactive CYP1A2 content were not significant. 4. Proguanil activation was inhibited by R,S-mephenytoin, troleandomycin and by inhibitory anti-CYP3A antiserum and anti-CYP2C IgG and was activated by alpha-naphthoflavone. Inhibitors selective for CYP1A2, CYP2E1, CYP2A6 or CYP2C9/10 had little or no effect on proguanil activation. The extents of inhibition by R,S-mephenytoin, troleandomycin and the two antibodies varied with the immunoreactive CYP3A content of the microsomes used. 5. It is concluded that proguanil activation to cycloguanil by human liver microsomes is mediated both by S-mephenytoin hydroxylase and isoforms of the CYP3A subfamily. This has implications for the use of proguanil as an in vivo probe for the S-mephenytoin poor metaboliser phenotype.

Caffeine (CA) N1-, N3- and N7-demethylase, CA 8-hydroxylase and phenacetin O-deethylase activities were measured in microsomes from 18 separate human livers which had been characterized previously for a range of cytochrome P450 (CYP) isoform-specific activities and immunoreactive CYP protein contents. Correlations between the high affinity components of the three separate CA N-demethylations were highly significant (r = 0.77–0.91, P < 0.001) and each of the three high affinity CA N-demethylations correlated significantly (r = 0.64–0.93, P < 0.05-0.001) with the high affinity phenacetin O-deethylase, 2-acetylaminofluorene N-hydroxylation and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) mutagenicity (all predominantly CYP1A2-mediated reactions). Consistent with these observations, cDNA-expressed human CYP1A2 catalyzed the N1-, N3- and N7-demethylation of CA and apparent Km values were similar (0.24–0.28 mM) for all three reactions and comparable to those observed previously with human liver microsomes. The low affinity components of CA N1- and N7-demethylation correlated significantly (r = 0.55–0.85, P < 0.05-0.001) with immunoreactive CYP2E1 content and the CYP2E1-specific activities 4-nitrophenol and chlorzoxazone hydroxylation. Diethyldithiocarbamate, a selective inhibitor of CYP2E1, inhibited the low affinity CA N1- and N7-demethylation, with IC50 values of 23 μM and 11 μM, respectively. The apparent Km values for CA N1- and N7-demethylation by cDNA-expressed CYP2E1 (namely 28 and 43 mM, respectively) were of a similar order to those calculated for the low affinity microsomal activities. Significant correlations (r = 0.87–0.97, P < 0.001) were observed between CA 8-hydroxylation and immunoreactive CYP3A content and the CYP3A-mediated reactions benzo(a)pyrene hydroxylation, omeprazole sulfoxidation and aflatoxin B1 mutagenesis. Effects of α-naphthoflavone, erythromycin, troleandomycin and nifedipine on microsomal CA 8-hydroxylation were generally consistent with CYP3A involvement. Taken together with previous data, the results indicate a major involvement of CYP1A2 in the high affinity component of all three human hepatic CA N-demethylations. In contrast, CYP2E1 appears to be the main enzyme involved in the low affinity components of CA N1- and N7-demethylation while CA 8-hydroxylation is catalysed predominantly by a CYP3A isoform(s).