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Biomedical subjects

M Rapp

Publications and source records attributed to M Rapp.

63 records · Page 4Linked to original sources
PubMed1985

Estrogen receptor in bovine skeletal muscle.

In connection with investigations of the anabolic action of estrogens, we examined skeletal muscle of veal calves for estradiol receptors. The high speed supernatant of muscle homogenate was incubated with .5 nM 3H-estradiol and for the determination of nonspecific binding with .5 nM 3H-estradiol plus 13 nM estradiol at 0 C overnight. After treatment with charcoal two times, the supernatant was analyzed by agar gel electrophoresis. Specific binding was found in the typical position of cytosolic estradiol receptor. Ninety percent of 3H-estradiol binding was suppressed by estradiol-17 beta, zeranol, estrone or diethylstilbestrol, but was not affected by testosterone, dihydrotestosterone, trenbolone or progesterone. The specific binding activity varied between .3 and 2.0 fmol/mg protein and the dissociation constant of the receptor was Kd = 60 pM. After an enrichment up to 42 fmol/mg cytosolic protein using heparin sepharose, the receptor remained unchanged as determined by agar gel electrophoresis. Although uterine tissue generally contains 1,000 times more estradiol receptors, these results clearly demonstrate that skeletal muscle also contains estradiol receptors with identical properties. This indicates that one possible component of the anabolic action of estrogens may be the direct stimulation of the muscle via the estradiol receptor.

Animals↗
PubMed1977

Nonpairing of the X and Y chromosomes in the spermtocytes of BDF1 mice.

In the hybrid mouse strain BDF1, some 35--40% of spermatocytes had unpaired X and Y choromosomes in stages ranging from diplotene to first meiotic metaphase. This phenomenon varied significantly from mouse to mouse. In pooled material from Swiss Albino and CF1 mice, the corresponding frequency was 5.7%. In C57 BL/6 mice, one of the parent strains of BDF1 mice, the X and Y were separate in 7.7% of the spermatocytes. Based on the behavior of the X and Y in the BDF1 strain, it is concluded that they do not pair, rather than initially pairing and then precociously separating. The factor interfering with the pairing of the X and Y does not affect the autosomes; possibly it is an incompatibility of the two sex chromosomes, which come from different inbred lines.

Animals↗
PubMed1977

The effect of procarbazine on the chromosomes of normal and malignant mouse cells.

The effects of the cancer drug methylhydrazine derivative procarbazine (PC) on the chromosomes of normal and malignant cells in the mouse strains Swiss Albino, CF1, and BDF1 have been analyzed. PC broke chromosome in the hypotetraploid Ehrlich and the diploid P388 ascites tumors. Practically all breaks seemed to be of the G2 type and, as far as could be determined, took place in the quinacrine-dark or the corresponding Giemsa-light regions. The vast majority of the broken ends had rejoined to form chromatid translocations. No increase in chromosome breaks were seen in any of the normal tissues treated in vivo: spleen, bone marrow, spermatocytes, or spermatogonia (in this tissue the cells were not counted). The chromosomes of the Ehrlich ascites tumor have been studied by means of both Q-banding and G-banding. Very few, if any, chromosomes seem to have an exact homologue or to correspond to any of the normal mouse chromosomes.

Animals↗
PubMedDate not supplied

Application to a cartilage targeting strategy: synthesis and in vivo biodistribution of (14)C-labeled quaternary ammonium-glucosamine conjugates.

As part of a cartilage targeting program based on the affinity of the quaternary ammonium (QA) moiety for cartilage, QA derivatives of D-glucosamine (DG), an antirheumatic drug exhibiting a natural tropism for cartilaginous tissues, were designed and evaluated by pharmacokinetic studies. Two QA-DG conjugates were synthesized and labeled with (14)C by cross-linking the QA entity (trimethylammonium or pyridinium) to [(14)C]DG via an amide bond in a two-step procedure. After intravenous injection to male Sprague-Dawley rats, the two (14)C-labeled conjugates exhibited similar pharmacokinetic profiles, but their behavior clearly differed from that of unconjugated DG in several ways. (i) The tissue distribution for the conjugates was more restricted, with a decreased radioactivity level for whole tissues except for kidney, cartilage, and skin. (ii) The radioactivity concentrated more rapidly and strongly in cartilage for the conjugates than for DG for the short times after injection; on the other hand, 1 h after administration, the radioactivity level in cartilage was higher for DG, this result being consistent with the tropism already observed for this compound. (iii) Both conjugates were eliminated predominantly by the urinary route (85%); the radioactivity level in urine for DG was lower (45% of the injected dose), and significant (14)CO(2) was found in expired air, indicating metabolization and utilization of DG for energy-consuming processes. (iv) Blood and plasma kinetics studies displayed an enterohepatic cycle for DG, whereas for the QA conjugates, a rapid disappearance was observed. (v) HPLC analyses of plasma and urine indicated a low degree of metabolization for the conjugates, most of the radioactivity recovered in urine and plasma corresponding to the unchanged molecule. This study demonstrates that the introduction of the QA moiety on DG modifies its biodistribution and lends it a greater specificity for cartilage, at least for short times after injection. These findings justify further work on QA derivatives of other antirheumatic agents.

Animals↗
PubMedDate not supplied

Control of illegal medroxyprogesterone acetate-application in veal calves by residue analysis in adipose tissue using HPLC/RIA methods.

Procedures for the determination of medroxyprogesterone acetate (MPA) in adipose tissue collected at time of slaughter allowing the control of MPA application to veal calves are described. Screening radioimmunoassays after sample clean-up were sufficient for a first survey of MPA treatments in livestock herds. Validation of all positive samples was performed by two-dimensional (silica gel diol phase and RP-18 phase) HPLC/RIA immunograms. Megestrol acetate and melengestrol acetate with cross-reactivities of 31% and 0.3% respectively were clearly separated by the RP HPLC. With an absolute detection limit of 4 pg MPA/tube (90% relative binding) negative control samples did not exceed 6 pg/tube, equivalent to 6 pg/g fat in the validating method. Seventeen days after intramuscular (i.m.) injection of 24 mg MPA only 32 pg MPA/g fat were found, while i.m. injection of 60 mg MPA and a waiting period of 19 days resulted in 2700 pg MPA/g fat. After feeding two calves 20 micrograms MPA per head daily for 1 week followed by 200 micrograms MPA per head daily for 2 weeks 359 and 468 pg MPA/g fat were measured. In plasma as well as in adipose tissue more than 80% of the whole immunoreactive material was MPA itself, without indications for the presence of cross-reacting MPA metabolites as confirmed by HPLC/RIA immunograms. Based on day of slaughter ratios of accumulation of MPA from plasma into fat of MPA-fed veal calves were 52 and 72 respectively. In urine MPA was only detectable a few days after injection; as compared to a plasma concentration of 950 pg MPA/ml the amount in urine was only 37 pg MPA/ml and also 325 pg unidentified MPA-equivalents/ml.

Adipose Tissue↗
PubMedDate not supplied

A brief history of time (constants).

That the cerebral cortex processes information at prodigious speeds cannot be doubted. Yet the passive time constant, tau(m), of neurons, often thought of as a measure of the neuron's "response time' to synaptic input, is relatively long. In the 1950s, tau(m) was estimated to be only a few milliseconds for mammalian central neurons; with improvement in recording techniques, its estimated value grew over the years and it now stands near 20-100 msec. However, as we will argue here, the functional meaning of tau(m) is ambiguous. On the basis of a newly introduced definition of local delay, we show that the time window for synaptic integration in passive dendritic trees can be much smaller than the time constant. We argue that the voltage response to very brief synaptic inputs is essentially independent of tau(m). We discuss how tau(m) can change dynamically with the global activity of the network, as well as the difficulties of defining a time constant in structures with voltage-dependent elements. We conclude that the classically defined tau(m) only provides a very rough estimate, typically an overestimate, of the response time of neurons and that alternative measures are required to capture the dependency of the time course of the membrane potential on ligand-gated and/or voltage-dependent membrane conductances.

Animals↗
PubMedDate not supplied

Disposition and metabolism of O6-alkylguanine-DNA alkyltransferase inhibitor in nude mice bearing human melanoma.

Tumor resistances to chloroethylnitrosourea (CENU) are mainly due to O6-alkylguanine-DNA alkyltransferase (AGT). Our laboratory has synthesized a new water-soluble AGT inhibitor. O6-benzyl-N-acetylguanosine (BNAG). We have shown that this compound is able to deplete AGT activity on M4Beu human melanoma cells and to enhance the antitumor power of CENU N'-[2-chloroethyl]-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) towards the M4Beu melanoma grafted on nude mice. With a view to determining the best combination BNAG/CENUs conditions, we have studied the distribution and metabolism of BNAG in nude mice bearing M4Beu human melanoma. BNAG, labelled with carbon-14 on the benzyl group, was administered by single i.v. dose of 40 mg/kg. Blood analysis showed that the main radioactive compound was unchanged molecule, and only a small part was found as hippuric acid resulting from the metabolic cleavage of the benzyl group. BNAG and hippuric acid were mainly eliminated in the urine. Unchanged BNAG blood kinetics showed three phases: blood epuration (t1/2 (1) = 13 min), reabsorption and elimination (t1/2 (2) = 1.7 hr). This kinetic profile is probably due to an enterohepatic cycle. BNAG is distributed in several tissues (kidney, liver, skin, duodenum, colon, tumor) but not in the central nervous system, suggesting a poor blood-brain crossing. Because an important part of the administered dose is not metabolized, high unchanged BNAG level remains in most tissues, including M4Beu tumor, and AGT depletion can occur several hours after dosing.

Animals↗
PubMedDate not supplied

Main urinary metabolites of two cysteamine-containing 2-(chloroethyl) nitrosoureas in rats.

Urine is the major route of excretion of N'-(2-chloroethyl)-N-[2-(methylsulfinyl)ethyl]-N'-nitrosourea (CMSOEN2), N'-(2-chloroethyl)-N-[2-(methylsulfonyl)ethyl]-N'-nitrosourea (CMSO2EN2), and their metabolites in the rat. Labeling the two compounds with 14C in three different positions facilitated their metabolic study in animals. The 14C-ethyl species were chosen in order to investigate the presence of unchanged compounds and that of the denitrosated forms. With the same 14C label position, we showed that isolated metabolites derived from this part of the molecule were degradation products of alkylated glutathione and/or cysteine. They are common to both CMSOEN2 and CMSO2EN2, namely thiodiacetic acid and its sulfoxide, the sum of which represents about half of urinary radioactivity. N-acetyl carboxymethylcysteine and N-acetyl hydroxyethylcysteine, accounting for approximately 6% to 7% of the eliminated 14C radioactivity, were also characterized. However, four minor metabolites corresponding to less than 10% of the excreted radioactivity remained unidentified. With the [14C]cysteamine and [14C]carbonyl labels related to the isocyanate moiety behavior, we indirectly showed that more than 60% to 70% of the excreted metabolites were carbamoylation products of endogenous substrates. A small amount of free amines, 2-methylsulfinylethylamine and/or 2-methylsulfonylethylamine, representing 15%-16% of the eliminated radioactivity, was also detected. The total data confirm the predominant function of glutathione and/or cysteine in the detoxifying system of the chloroethyl moieties and reveal the unexpected but important role played by carbamoylation reactions in the metabolic fate of the drug isocyanate moieties.

Animals↗