Consensus agreement regarding protocol issues discussed during the mouse lymphoma workshop: Portland, Oregon, May 7, 1994.
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Animals↗
Biomedical subjects
L Müller
Publications and source records attributed to L Müller.
OTC pharmaceuticals and genotoxicity testing: the paracetamol, anthraquinone, and griseofulvin cases.
Genotoxic effects are hardly assessable in an exposed population but are generally considered to be serious due to their unpredictable effects on subsequent generations and to the link between genotoxicity and cancer. Lack of knowledge about a genotoxic/carcinogenic potential has to be stated for numerous compounds which are often in pharmaceutical use known for a long time. A thorough testing programme like it is done for new compounds is essential for such compounds that are not completely unsuspicious with respect to being reactive with macromolecules or that have the potential to generate reactive metabolites in the body. Paracetamol, anthraquinone-containing preparations, and griseofulvin are examples for pharmaceuticals that have been in use for a long time but for which genotoxicity testing revealed a possible deleterious potential only recently. The Federal Health Office/Federal Institute for Drugs and Medical Devices therefore imposed new studies upon companies marketing these compounds in the last years. These studies in part led to a more thorough description of possible adverse effects or even restrictions for use. Paracetamol exhibits a genotoxic potential in vitro and in vivo probably via indirect, cytotoxicity or enzyme inhibition-mediated effects. Further studies will have to clarify whether a threshold could be established and whether effects do not occur at therapeutic dose levels. Genotoxicity data on the mixed group of anthraquinones reveal positive and negative findings. Compounds such as lucidin, danthron, emodin supposedly have a genotoxic and carcinogenic potential. Further studies with anthraquinone-containing plant preparations will have to clarify the content and genotoxic activity of the preparations and the active ingredients. Lucidin- and danthron-containing preparations are currently no longer in use now whereas restrictions apply for other anthraquinone-containing laxatives. Griseofulvin is acknowledged in the meantime as an aneugen for somatic and germ cells. It is in vitro effective in concentrations that correspond to therapeutic plasma levels.
Acetaminophen↗
Evaluation studies on the in vitro rat hepatocyte micronucleus assay.
Based on a previous study with 8 chemicals (Müller et al., 1993) the applicability of the in vitro rat hepatocyte micronucleus assay was evaluated by testing a further 21 compounds of different chemical classes. The obtained results are in good agreement with the known genotoxic profiles of about 90% of the in total tested compounds. Several known mutagens and carcinogens, i.e., alkylating agents, aromatic amines, nitrosamines, nitro compounds, cross-linking agents, and pyrrolizidine alkaloids gave clear positive results in this assay, whereas all of the tested non-carcinogens were negative. The hepatocyte micronucleus assay was shown to distinguish between carcinogenic/non-carcinogenic isomers, such as 2- and 4-acetylaminofluorene (AAF) and 2- and 1-nitropropane (NP). Furthermore, the non-genotoxic nature of several hepatocarcinogens, i.e., the peroxisome proliferating agents fenofibrate, nafenopin, Wy-14,643, diethyl(hexyl)phthalate (DEHP), and the sedative phenobarbital, could be confirmed in this assay. The hepatocarcinogen coumarin exerted mitogenic but no mutagenic properties in the rat hepatocyte micronucleus assay. This compound may act as a liver tumor promoter. Benzo[a]pyrene (B[a]P) and 7,12-dimethylbenzanthacene (DMBA), both belonging to the group of known carcinogenic and mutagenic polycyclic aromatic hydrocarbons, failed to induce micronucleus formation in rat hepatocytes. The high susceptibility of in vitro proliferating hepatocytes to mitotic inhibition, exerted by the strong cytotoxic actions of these compounds, seems to be responsible for these negative results. A strongly reduced mitotic activity can prevent the formation of micronuclei, even when clastogenic effects may have occurred. In the present stage, the in vitro rat hepatocyte micronucleus assay cannot be recommended for screening genotoxicity testing. It should rather be used for special purposes, e.g., when liver-specific mutagenic effects are expected.
Animals↗
Synthesis of [18F]NNC 12-0817 and [18F]NNC 12-0818; two potential radioligands for the dopamine transporter.
The preparation of no-carrier-added 18F labelled NNC 12-0817 (1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-[4-oxo-4-(2- thienyl)butyl]piperazine) and NNC 12-0818 (1-(2[bis(4- fluorophenyl)methoxy]ethyl)-4-]4-hydroxy-4-(2-thienyl)butyl]piperazine) is described. NNC 12-0818 is the designation of the racemic mixture of two enantiomers. Fluorine-18 is introduced into 4-[18F]fluoro-4'-fluorobenzophenone from the corresponding triflate salt by a nucleophilic aromatic substitution reaction. A no-carrier-added synthesis was performed in 6 steps starting from N,N-dimethylaniline and 4-fluorobenzoyl chloride giving [18F]NNC 12-0817 and [18F]NNC 12-0818 in good yields and a radiochemical purity after HPLC-purification higher than 99%.
Carrier Proteins↗
Improved synthesis of some commonly used PET radioligands by the use of [11C]methyl triflate.
[11C]Methyl triflate was compared with [11C]methyl iodide as a labelled precursor in the synthesis of some commonly used PET radioligands, L-[11C]deprenyl, [11C]m-hydroxyephedrine (MHED), [11C] beta-CIT, [11C] beta-CFT and [11C]SCH 39166 which have been prepared previously in comparatively low yields from [11C]methyl iodide. A new dopamine reuptake radioligand, [11C] alpha-CIT, was also prepared. The results demonstrate that higher yields are obtained with shorter reaction times, lower reaction temperatures and smaller amounts of precursors with [11C]methyl triflate.
Benzazepines↗
Synthesis and binding properties of [3H]NNC 12-0781, a new radioligand for the dopamine reuptake system.
The tritiated dopamine reuptake inhibitor [3H]NNC 12-0781 ([1-[2-(bis(4-fluorophenyl)-methoxy)-ethyl]-4-(3-(2-furanyl)-2,3-[3H] - propyl)-piperazine) was radiolabelled in one step starting from 1-[2-(bis(4-fluorophenyl)-methoxy)-ethyl]-4-(3-(2-furanyl)-2-propenyl)- piperazine, using tritium gas and PdO as catalyst. The radiochemical purity of [3H]NNC 12-0781 was higher than 99% after HPLC purification with a specific radioactivity of 21 Ci/mmol. [3H]NNC 12-0781 bound specifically to rat striatum in vitro at +4 degrees C with a Kd of 1.76 nM and Bmax of 587 fmol/mg tissue. The nonspecific binding was about 10% at Kd. At +37 degrees C no acceptable binding was observed. The association of [3H]NNC 12-0781 thus has the characteristics of a radioligand for the dopamine transporter in vitro at +4 degrees C.
Animals↗
Comparison of [11C]methyl triflate and [11C]methyl iodide in the synthesis of PET radioligands such as [11C]beta-CIT and [11C]beta-CFT.
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Carbon Isotopes↗
76Br-beta-CBT, a PET tracer for investigating dopamine neuronal uptake.
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Animals↗
Body fat assessment by a new bipedal bioimpedance instrument in normal weight and obese women.
The aim of the study was to evaluate a new bioimpedance method for assessment of body fat employing bipedal electrodes instead of those attached to both upper and lower extremities. The new analyzer (TBF-105, Tanita Corp., Tokyo, Japan) enables simultaneous measurements of body weight and total body resistance in a subject standing on the stainless steel electrodes. The instrument was tested in both normal weight and obese women. Fat mass estimated by bipedal bioimpedance was highly correlated with that determined by hydrodensitometry (n = 145, r = 0.945, p < 0.001). Fat mass estimated by bipedal bioimpedance significantly correlated not only with subcutaneous fat measured as a sum of 10 skinfolds (r = 0.758, p < 0.001) but also with visceral fat determined as an area on CT scan (r = 0.780, p < 0.001). Anthropometric variables did not substantially influence the differences revealed in fat mass determined by bipedal bioimpedance and by densitometry. An overestimation of total fat mass by bipedal bioimpedance has not been revealed in severely obese individuals, even in those with higher fat accumulation in the limb region. In conclusion, our data have demonstrated that the new bioimpedance instrument employing bipedal electrodes represents a reliable tool for rapid body fat assessment in both normal weight and obese women.
Adipose Tissue↗
LRG1 is expressed during sporulation in Saccharomyces cerevisiae and contains motifs similar to LIM and rho/racGAP domains.
We here report the sequence of a yeast gene LRG1 whose deduced amino acid sequence contains sequence motifs similar to LIM domain proteins in the amino-terminal, and to rho/rac GTPase activating proteins (rho/racGAP's) in the carboxy-terminal part. LRG1 expression is differentially regulated showing a peak of expression in sporulating cells. Gene disruption experiments indicate that the gene is not essential and may play a role during mating.
Amino Acid Sequence↗
PET study of [11C]beta-CIT binding to monoamine transporters in the monkey and human brain.
The cocaine congener beta-CIT has been labeled with 11C for positron emission tomographic (PET) studies of the dopamine transporter. In the present autoradiographic study on human brain sections and PET study on monkey and human [11C]beta-CIT accumulated markedly in the striatum. [11C]beta-CIT binding in the striatum was selective to the dopamine transporter. The binding in the thalamus was on an intermediate level and was displaced by compounds having affinity for norepinephrine and serotonin transporters. The neocortical binding was on a low level and could be displaced only by citalopram, a serotonin uptake inhibitor. A high dose of cocaine intravenously (7 mg/kg) induced a 50% occupancy of specific [11C]beta-CIT binding to the dopamine transporter in the striatum. This dose is much higher than the doses of 0.25-0.5 mg/kg i.v. for cocaine arousal in human subjects. The finding indicates that cocaine arousal may be induced at a low dopamine transporter occupancy of a few percent. [11C]beta-CIT should be a useful radioligand to explore cocaine actions in humans and to follow the pathophysiological process in vivo by PET in neurodegenerative diseases of the striatum.
Adult↗
Preparation of a potential positron emission tomographic radioligand for the dopamine transporter.
NNC 12-0722 (1-[2-(bis(4-fluorophenyl)-methoxy)ethyl]-4-methyl piperazine) is a new selective inhibitor of the dopamine transporter. [11C]NNC 12-0722 was prepared by N-methylation of the desmethyl compound with [11C]methyl iodide. The total radiochemical yield of [11C]NNC 12-0722 was 40%-50% with an overall synthesis time of 30-35 min. The radiochemical purity was higher than 99% and the specific radioactivity about 1500 Ci/mmol (55 GBq/mumol). Autoradiographic examination of [11C]NNC 12-0722 binding on whole hemisphere cryosections from human brain post mortem demonstrated specific binding in the caudate nucleus and putamen. In a positron emission tomographic examination of [11C]NNC 12-0722 in a cynomolgus monkey there was a rapid uptake of radioactivity in the brain. In the striatum, a region with a high density of dopamine transporters, the radioactivity was two times higher than in the cerebellum. These results indicate that [11C]NNC 12-0722 may be a useful radioligand for labelling of the dopamine transporter in man.
Animals↗
Unambiguous through-bond sugar-to-base correlations for purines in 13C,15N-labeled nucleic acids: the HsCsNb,HsCs(N)bCb, and HbNbCb experiments.
A set of three 3D (1H,13C,15N) triple-resonance correlation experiments has been designed to provide H1'-H8 intraresidue sugar-to-base correlations in purines in an unambiguous and efficient manner. Together, the HsCsNb, HsCs(N)bCb, and HbNbCb experiments correlate the H1' sugar proton to the H8 proton of the attached base by means of the (H1', C1', N9, C8, H8) heteronuclear scalar coupling network. The assignment strategy presented here allows for unambiguous H1'-H8 intraresidue correlations, provided that no two purines have both the same H1' and C1' chemical shifts and the same C8 and N9 chemical shifts. These experiments have yielded H1'-H8 intraresidue sugar-to-base correlations for all five guanosines in the [13C,15N] isotopically labeled RNA duplex r(GGCGCUUGCGUC)2.
Base Sequence↗
The genotoxic potential in vitro and in vivo of the allyl benzene etheric oils estragole, basil oil and trans-anethole.
Estragole, trans-anethole and basil oil were tested for their ability to induce DNA repair in rat hepatocytes in vitro and in rat liver in an ex vivo test. There was a marked induction of UDS by estragole and basil oil in vitro (LOEC about 10(-5) mol/l). The basil oil we used contained about 88.2% estragole. It is evident from our results that the induction of UDS with basil oil could be directly related to its main constituent estragole. trans-Anethole was only slightly effective in the in vitro UDS test. The ex vivo UDS test led to clearly elevated DNA repair for estragole and basil oil in rats treated orally with doses up to 2 g/kg body weight. Estragole was not positive in a chromosomal aberration test with V79 cells either via direct treatment, with rat liver S9 mix or with rat hepatocytes as source of metabolism.
Allylbenzene Derivatives↗
[Evaluating the noise problem in regional town planning].
While looking for enough living quarters for the town people regional planners are often confronted with high levels of noise due to traffic, highways and railways near the planning area. This may change or even stop the procedure of town planning. Generally, health authorities--who are more or less involved in the process of planning--should take the chance to demand compatibility of special planning with health care regarding noise. However, most guidelines on health-compatible noise levels are not legally binding. This paper describes the variety of health problems accompanied by moderate to high levels of noise. In regions with traffic noise problems efforts should be directed at maximum health compatibility coupled to highly imaginative planning. It is suggested that levels of noise of 55 dB(A) (daytime) and of 45 dB(A) (nighttime) should be tolerated near to the building. This would ensure tolerable levels of noise of 35 dB(A) (daytime) and of 30 dB(A) (nighttime) in the dwellings. Examples of different arrangements of buildings are shown. They demonstrate that these tolerable noise levels could even be observed in areas with traffic problems. It mostly depends on the planner's imagination whether the need for dwelling houses in problem areas could be met in keeping with health demands.
Automobiles↗
Speech production changes with the use of a multichannel cochlear implant in a postlingually hearing impaired adult.
Profoundly deaf cochlear implant users provide an interesting population in which to assess the role of distorted auditory feedback in speech, since their electrically stimulated hearing is significantly different from normal hearing. The aim of the study was to evaluate, by means of spectrographic and listener analyses, the speech production changes in a postlingually deafened adult with the use of a multichannel cochlear implant over time, compared to that of hearing aids as well as no-amplification. The results indicated significant improvements in the use of suprasegmental speech features as well in the production of specific segmental features of speech.
Adult↗
An assessment of the in vitro hepatocyte micronucleus assay.
The in vitro hepatocyte micronucleus assay was tested for its practicability and its usefulness in detecting mutagens. The assay protocol developed by Alati et al. (1989) was shown to give reproducible levels of proliferating hepatocytes and the formation of micronuclei could be readily assessed by fluorescence microscopy. Epidermal growth factor and insulin were used as mitogens, yielding mitotic indices of 2.4 +/- 0.74% after 72 h of culture. The high number of 8.0 +/- 3.33% micronucleated hepatocytes in control cultures at that time, typically for in vitro stimulated hepatocytes, is probably due to disordered mitoses frequently leading to chromosome loss. The direct acting mutagen N-methyl-N'-nitro-N-nitrosoguanidine and the clastogens cyclophosphamide and retrorsine, which require metabolic activation, induced dose dependent increases in the frequencies of micronucleated hepatocytes. The carcinogen 2-AAF also yielded significantly enhanced rates of micronuclei. The non-mutagen KCl as well as the peroxisome proliferator clofibrate, which is considered to be a non-genotoxic hepatocarcinogen, yielded consistently negative results. Problems occurred when chemicals exerting strong cytotoxic effects were tested in this assay. The mutagen and hepatocarcinogen aflatoxin B1 did not enhance the number of micronucleated hepatocytes. Rather a reduction of micronuclei and of mitoses was observed at AFB1 concentrations considered positive in other genotoxicity assays. Hepatocyte proliferation seems to be highly susceptible to the cytotoxic action of chemicals. A decrease in the proliferating activity of hepatocytes can obviously prevent the detection of mutagenic effects. Further studies on the in vitro hepatocyte micronucleus assay are necessary to clarify its role in mutagenicity testing.
Animals↗
[11C] beta-CIT, a cocaine analogue. Preparation, autoradiography and preliminary PET investigations.
beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) is a cocaine analogue with a high affinity for the dopamine transporter. [11C] beta-CIT was prepared by N-methylation of nor-beta-CIT with [11C]methyl iodide. The total radiochemical yield of [11C] beta-CIT was 40-50% with an overall synthesis time of 35-40 min. The radiochemical purity was > 99% and the specific radioactivity at the time of injection was about 1000 Ci/mmol (37 GBq/mumol). Autoradiographic examination of [11C] beta-CIT binding in human brains post-mortem demonstrated a high level of specific binding in the striatum. PET examination of [11C] beta-CIT in a Cynomolgus monkey showed a marked accumulation of radioactivity in the striatum. The ratio of radioactivity in the striatum-to-cerebellum approached 5 after 87 min. In a displacement experiment, radioactivity in the striatum but not in the cerebellum, was markedly reduced after injection of unlabelled cocaine. [11C] beta-CIT has a potential as ligand for PET examination of cocaine effects in man.
Animals↗