PubMed Health⌕ Search

Biomedical subjects

K G Jensen

Publications and source records attributed to K G Jensen.

At least 19 recordsLinked to original sources
PubMed1999

In vitro metabolism of the M1-muscarinic agonist 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine by human hepatic cytochromes P-450 determined at pH 7.4 and 8.5.

Biotransformation of the M1-muscarinic agonist Lu 25-109 (5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine) , in development for the treatment of Alzheimer's disease, was investigated to obtain information on the identity of human hepatic cytochrome P-450 enzymes involved in its metabolism. The identification of these P-450s was accomplished through studies using 1) simple regression analysis with 14 phenotyped human liver samples, 2) selective chemical inhibitors, and 3) microsomes containing cDNA-expressed enzymes. The production of some metabolites is enhanced in vitro when the pH of the incubation media is shifted from pH 7.4 to 8.5. The metabolite production in human liver microsomes was NADPH-dependent, suggesting that the metabolism of Lu 25-109 in human liver microsomes is primarily P-450-dependent. Lu 25-109 was metabolized by human liver microsomes to Lu 31-126 (de-ethyl Lu 25-109) mainly by CYP2D6; to Lu 29-297 [3-(2-ethyltetrazol-5-yl)-1-methyl-pyridinium] and Lu 25-077 (demethyl Lu 25-109) mainly by CYP1A2, CYP2A6, CYP2C19, and CYP3A4; and to Lu 32-181 (Lu 25-109 N-oxide) by CYP1A2 and possibly by CYP2C19. One metabolite, Lu 32-181 (N-oxide), could be reduced back to Lu 25-109, a reaction not inhibited by the applied cytochrome P-450 inhibitors. This study did not indicate any involvement of FMO3 or MAO in the in vitro metabolism of Lu 25-109 in human liver microsomes.

Cytochrome P-450 Enzyme System↗
PubMed1996

The detection and evaluation of aneugenic chemicals.

Although aneuploidy makes a significant contribution to both somatic and inherited disease the mechanisms by which environmental chemicals may induce numerical chromosome aberrations are only poorly defined. The European Union Project was aimed to further our understanding of those chemical interactions with the components of the mitotic and meiotic cell division cycle which may lead to aneuploidy and to characterise the parameters such as cellular metabolism which may influence the activity of aneugenic chemicals. C-mitosis can be induced by the highly lipophilic polychlorinated biphenyl and the completion of mitosis and cleavage can be modified by agents which deplete cellular levels of reduced glutathione. Modifications of the fidelity of chromosome segregation were produced by inhibiting the functioning of topoisomerase II during chromatid separation. In contrast, the modification of centromere integrity resulted in chromosome breakage as opposed to disturbance of segregation. Modifiers of tubulin assembly and centriolar functioning in somatic cells such as acrylamide, vinblastine and diazepam reproduced their activity in rodent bone marrow and male germ cells. The analysis of chromosome malsegregation in Aspergillus nidulans by a structurally related series of halogenated hydrocarbons was used to develop a QSAR model which had high predictive value for the results of fungal tests for previously untested related chemicals. Metabolic studies of potential aneugens in genetically engineered human lymphoblastoid cells demonstrated the detoxification of the aneugenic activity of chloral hydrate and the activation of 2,3-dichlorobutane, 1,1,2-trichloroethane and trichloroethylene by Phase I biotransforming enzymes. Cell transformation studies in Syrian hamster dermal cultures using a panel of 22 reference and or potential aneugens indicated that 15 of the 22 produced positive results following single exposures. Five of the aneugens which were negative following single exposures produced positive results where cultures were continuously exposed for up to 6 weeks to low concentrations following a single non-transforming exposure to the mutagen dimethyl sulphate. The transformation studies indicate that a significant proportion of chemical aneugens are potential complete carcinogens and/or co-carcinogens. To optimise the enumeration of chromosomes following exposure to potential chemical aneugens whole chromosome paints and centromere specific probes suitable for use in fluorescence in situ hybridisation (FISH) were developed for the rat, mouse and Chinese hamster and selected human probes evaluated for their suitability for routine use. Molecular chromosome probes were used to develop protocols for enumerating chromosomes in metaphase cells and centromeres and micronuclei in interphase cells. The analysis of segregation of specific centromeres in binucleate cells following cytochalasin B treatment was shown to be a potentially valuable system for characterising non-disjunction following chemical exposure. Whole chromosome paints and centromere specific probes were used to demonstrate the presence of dose-response thresholds following treatment with a reference panel of spindle inhibiting chemicals. These data indicate that the FISH technology is suitable for evaluating the relative hazards of low-dose exposures to aneugenic chemicals.

Aneuploidy↗
PubMed1996

Paracetamol-induced spindle disturbances in V79 cells with and without expression of human CYP1A2.

Spindle disturbing effects in terms of c-mitosis and cytotoxicity of paracetamol were investigated in two Chinese hamster V79 cell lines, one of which (V79MZh1A2) was transfected with human CYP1A2. This enzyme catalyses the oxidative formation of the reactive paracetamol metabolite, NAPQI, believed to initiate hepatoxicity by covalent binding to proteins after overdose. In the native V79 cell line paracetamol increased c-mitosis frequency in a concentration dependent manner from 8.7 + or - 3.5% (control) to 66 + or - 18% at 20 mM. A significant increase to 13.3 + or - 3.5% was first seen at 2.5 mM in the native cell line (P<0.05). In the V79MZh1A2 cells the concentration-effect curve was slightly shifted to the left (P<0.05) with c-mitosis frequency increased to 12.1 + or - 2.6% (P<0.05) at 1 mM paracetamol. At 5 mM paracetamol the c-mitosis frequency was 14.4 + or - 5.0% and 19.0 + or - 3.8% in the native and CYP1A2 expressing cell lines, respectively (P<0.05). At 20 mM paracetamol the c-mitosis frequency was 61 + or - 10% in the V79MZh1A2 cells. Cell survival was reduced to approximately 50% at 5-10 mM paracetamol in both cell lines. At 20 mM paracetamol survival was further decreased to 39 + or - 9% in V79MZh1A2 cells only (P<0.05). The present study demonstrated that paracetamol may disturb the spindle of dividing cells conveying a risk of aneuploidy. The spindle disturbing effect was only slightly enhanced by expression of CYP1A2, suggesting that metabolic activation plays only a minor role in this genotoxic effect. The reduction of survival mirrored the increase in c-mitosis frequency.

Acetaminophen↗
PubMed1995

Kinetics and inhibition by fluvoxamine of phenacetin O-deethylation in V79 cells expressing human CYP1A2.

The kinetics of phenacetin O-deethylation and its inhibition by fluvoxamine was investigated in a V79 cell line (V79MZh1A2) transfected with human CYP1A2. In four sets of experiments the apparent Km values for phenacetin O-deethylation ranged from 35 to 95 microM and the Ki for fluvoxamine-mediated inhibition of the reaction ranged from 2.7 to 14.5 nM, i.e. comparable to values obtained in human liver microsomes. The kinetic performance of the V79MZh1A2 cell line demonstrates its usefulness as an analytical tool in a variety of toxicological and drug metabolism studies involving CYP1A2.

Acetaminophen↗
PubMed1993

Metabolism of phenacetin in V79 Chinese hamster cell cultures expressing rat liver cytochrome P4501A2 compared to isolated rat hepatocytes.

In a genetically engineered V79 cell line (XEMd-MZ) expressing rat cytochrome P4501A2 the activity of phenacetin-O-deethylase was determined and compared with freshly isolated rat hepatocytes. In the V79 cells the apparent Km was 0.99 microM (N = 4), compared to the high affinity Km (0.23 microM, N = 4) found in freshly isolated rat hepatocytes, where as the Vmax found in the XEMd-MZ cells (14.90 pmol/min/10(6) cells) corresponded to the Vmax for the high affinity site of the hepatocytes (18.2 pmol/min/10(-6) cells). The metabolic capacity of phenacetin was quantitatively comparable to that of freshly isolated hepatocytes on a cell to cell basis.

Animals↗
PubMed1993

Effects of benzo[a]pyrene and (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene on mitosis in Chinese hamster V79 cells with stable expression of rat cytochrome P4501A1 or 1A2.

The effect of bioactivation of benzo[a]pyrene (B[a]P) and (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-diol) on spindle disturbances and toxicity has been investigated in V79 Chinese hamster cells genetically engineered to express cytochrome P4501A1 (CYP1A1) and cytochrome P4501A2 (CYP1A2). B[a]P induces spindle disturbances in native V79 Chinese hamster cells. This effect was enhanced by the expression of CYP1A1 but not CYP1A2. The increased effect seen in the CYP1A1-expressing cell line could be brought back to the level seen in the native cell line by alpha-naphthoflavone in a dose-dependent manner. This strongly suggests that a CYP1A1-dependent metabolite, conceivably (+-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BPDE) accounts for the increased spindle disturbing effect. B[a]P-7,8-diol induced spindle disturbances at remarkably low concentrations, 10(-8) M, irrespective of expression of the two CYPs. Our data suggest that B[a]P-7,8-diol is the most potent spindle-disturbing metabolite, whereas BPDE is the most important metabolite concerning mutagenesis. The concentrations inducing spindle disturbances correspond to those that are positive in mutation assays. We hypothesize that B[a]P is a complete carcinogen because of its ability to induce both aneuploidy and mutations after metabolic conversion of low non-cytotoxic concentrations.

Animals↗
PubMed1993

Effect of ascorbate and 5-aminosalicylic acid on light-induced 8-hydroxydeoxyguanosine formation in V79 Chinese hamster cells.

Recently we showed that ascorbate and 5-aminosalicylic acid (5-ASA) prevented 8-hydroxydeoxyguanosine (8-OHdG) formation in calf thymus DNA exposed to UV-visible light. However, the ultimate defense against oxidative DNA damage depends on an intracellular/intranuclear effect of the compounds. In the present study we investigated the effect of ascorbate and 5-ASA on 8-OHdG formation in V79 Chinese hamster cells exposed to light from a sun-lamp. Exposure for 1 min (4560 mJ/cm2) increased 8-OHdG formation in cellular DNA to 30-40 times background level. Preincubation of the cells with ascorbate or 5-ASA at concentrations of 0.1, 1 and 10 mM diminished the 8-OHdG formation to 0.67, 0.74 and 0.49 times controls (P < 0.05) for ascorbate respectively, and to 0.82, 0.66 and 0.33 times controls (P < 0.05), for 5-ASA. These findings demonstrate that both ascorbate and 5-ASA prevent oxidative DNA damage in cells by acting as intracellular/intranuclear antioxidants.

Aminosalicylic Acids↗
PubMed1991

Organotin compounds induce aneuploidy in human peripheral lymphocytes in vitro.

In vitro exposure of PHA-stimulated human lymphocytes to organotin compounds resulted in statistically significant increases in the frequencies of hyperdiploid cells. When taken together with our previous study demonstrating spindle inhibiting effects of the same organotin compounds by an indirect method (Jensen et al., 1989), the present study strongly indicates that organotin compounds are able to induce aneuploidy, probably by affecting spindle function.

Adult↗
PubMed1991

Effects of organotin compounds on mitosis, spindle structure, toxicity and in vitro microtubule assembly.

Di- and tri-methyl, -butyl and phenyl tin, all as chlorides were tested for toxicity and spindle disturbances in V79 Chinese hamster cells and for effects on in vitro assembly of bovine brain tubulin. The V79 cells were treated for 30 min and in general, loss of a stainable spindle could be demonstrated at slightly higher concentrations than c-mitosis. Both these effects were observed at low, non-toxic concentrations. The c-mitotic activity of the compounds was found to increase with increasing lipophilicity and it was best described by a regression on both lipophilicity (partition coefficient octanol/water) and loss of spindle stain. All compounds showed a concentration dependent inhibition of microtubule assembly and all but diphenyltin induced disassembly of preassembled microtubules. An effect on the rate of polymerization was suggested for tributyl- and triphenyltin. The results further indicate that the inhibition of microtubule assembly is through direct interaction with tubulin but does not involve the sulfhydryls of the protein. Thus, the organotins seem to act through two different cooperative mechanisms, inhibition of microtubule assembly and interaction with hydrophobic sites. The latter mechanism might involve Cl-/OH- exchange across cellular membranes. Previous studies have demonstrated chromosomal supercontraction and aneuploidy in human lymphocytes exposed to low concentrations of organotin in vitro and it is suggested that exposure to these compounds may increase the risk of aneuploidy in humans.

Animals↗
PubMed1988

Determination of ethylene oxide residues in processed food products by gas-liquid chromatography after derivatization.

A simple, sensitive and fast method (taking only 4-5 h) for the determination of residues of ethylene oxide (EO) and its reaction product, ethylene chlorohydrin (ECH), is described. For the analysis sodium hydroxide is added to the sample where ECH is transformed to EO. This is followed by the distillation of EO into dilute sulphuric acid containing sodium iodide, whereby EO is converted into ethylene iodohydrin (EIH). The EIH content is determined by gas chromatography using electron capture detection. The method has proved to be applicable to the analysis of low residue levels (less than 0.05 mg/kg, calculated as EO) in various foods, including processed foods. The collaborative studies carried out with four food products in six laboratories were remarkably successful with regard to repeatability of the method and reproducibility of the results. The recoveries of ECH were 50%-60%. In the 204 food products examined EO residues were found in 96 samples at concentration levels between 0.05 mg/kg and 1800 mg/kg.

Chlorohydrins↗
PubMed1988

Antihypertensive activity in a series of 1-piperazino-3-phenylindans with potent 5-HT2-antagonistic activity.

A series of trans-1-piperazino-3-phenylindans were synthesized with the goal of replacing their established neuroleptic profile with that of peripheral 5-hydroxytryptamine (5-HT2) antagonism. Compounds with an unsubstituted or fluoro-substituted 6-position in the indan ring, and which had a five- or six-membered heterocyclic ring attached by an ethylene chain to the piperazine ring, satisfied this objective. Some of the compounds had potent antihypertensive activity in conscious, spontaneously hypertensive rats (SHR). In pithed rats they antagonized the pressor effect induced by 5-HT in doses 100-1000 times lower than doses needed to antagonize the pressor effect of phenylephrine. The effect was stereoselective and associated with enantiomers with 1R,3S absolute configuration. 1S,3R enantiomers inhibited the uptake of dopamine and norepinephrine in vitro. The compound with the best antihypertensive activity was (+)-(1R,3S)-1-[2-[4-[3-(4-fluorophenyl)-1-indanyl]-1- piperazinyl]ethyl]-2-imidazolidinone (Lu 21-098, irindalone). Its pharmacological profile resembled that of the standard compound ketanserin. There was a close structural correspondence between ketanserin and irindalone in a conformation that we recently identified as a D-2 receptor-relevant configuration of its neuroleptic "parent" tefludazine. This suggests that the dopaminergic (D-2) and the serotonergic (5-HT2) pharmacophores are structurally closely related.

Animals↗
PubMed1986

Pesticide residues in black tea.

An investigation of residues of organochlorine and organophosphorous pesticides, as well as of a number of fungicides and of inorganic bromide in 99 samples of black tea taken on the Danish market is reported. The type of pesticide residues involved appear to be very uniform within each country of origin, whereas there are distinct differences between individual countries. Tea from Sri Lanka seems to contain less and fewer residues than tea from the other big tea producing countries. A great many of the samples contained alpha-HCH, lindane and DDT. The use of alpha-HCH and DDT is prohibited in Denmark. Only few other pesticides were detected and at a much lower frequency. None of the teas contained residues that may be regarded as being injurious to health.

Bromides↗
PubMed1985

Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial.

We conducted a double-blind randomized study of 132 patients to determine whether the new, investigational proton-pump inhibitor, omeprazole (30 mg per day), would accelerate healing and pain relief, as compared with cimetidine (1 g per day), in patients with duodenal ulcer. After two weeks of treatment, which was completed by all patients, the healing rates were 73 per cent in the omeprazole group and 46 per cent in the cimetidine group (P less than 0.01). After four weeks of treatment, which was completed by 118 patients, the corresponding figures were 92 and 74 per cent (P less than 0.05). In the omeprazole group 55 per cent of the patients were free of pain after the first week, as compared with 40 per cent of those treated with cimetidine (P greater than 0.05). No major clinical or biochemical side effects of omeprazole or cimetidine were noted. A six-month follow-up study revealed no significant difference between the recurrence rates after omeprazole and after cimetidine treatment. In May 1984 clinical trials with omeprazole were temporarily suspended, since a study of long-term toxicity in rats had shown the development of gastric carcinoid tumors.

Adult↗
PubMed1984

Additional antacid does not increase the effect of cimetidine in gastric ulcer disease.

Eighty-one adult outpatients with endoscopically confirmed gastric ulceration were treated with cimetidine (1 g/day). In addition, the patients were allocated at random to either intensive antacid treatment or placebo treatment. This part of the study was double-blind. It was found that additional antacid treatment had no effect on ulcer healing and symptoms in cimetidine-treated gastric ulcer patients. The results were similar in patients with corpus ulcers and patients with prepyloric ulcers.

Adult↗
PubMed1983

Freeze-fracture analysis of phloem structure in plant tissue cultures. III. P-Protein, sieve area pores, and wounding.

Phloem sieve elements in small nodules of callus tissue have open sieve pores and scattered P-protein when the tissue is fixed intact. Intentionally slicing the nodules prior to fixation results in the formation of wound responses, including an alteration in P-protein distribution and the formation of plugged sieve pores. Freeze-fracture replicas show well-preserved P-protein as randomly oriented filaments in intact sieve elements. Wounded sieve elements, however, demonstrate dense bundles of oriented P-protein filaments in freeze-fracture replicas. Open pores with few P-protein filaments are seen in replicas of undamaged sieve elements. These callus nodules can be used as a model system to investigate phloem structure, function, and wounding.

Cell Membrane↗