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Biomedical subjects

N Busch

Publications and source records attributed to N Busch.

At least 37 records · Page 2Linked to original sources
PubMed1994

The major metabolites of ursodeoxycholic acid in human urine are conjugated with N-acetylglucosamine.

Ursodeoxycholic acid (750 mg/day) was administered orally to ten healthy subjects over a period of 10 days; 24 hr urine samples were collected the day before and on the last day of the study. Urinary bile acids were extracted, separated into groups of conjugates and analyzed by gas chromatography-mass spectrometry and fast atom bombardment mass spectrometry. Excretion of ursodeoxycholic acid rose from 70 to 2,915 micrograms/24 h. The highest increase was observed among N-acetylglucosamine conjugates, 90% of which constituted the previously unknown double conjugate of ursodeoxycholic acid with N-acetylglucosamine and glycine. Excretion of isoursodeoxycholic acid increased from 50 to 738 micrograms/24 h. This isomerization product of ursodeoxycholic acid was excreted almost exclusively as N-acetylglucosamine conjugate. In total, N-acetylglucosamine conjugates constituted 50% of urinary metabolites of ursodeoxycholic acid. In addition, metabolites of ursodeoxycholic acid hydroxylated at carbon atoms 1, 6, 22 and possibly 21 were observed. These compounds were also found as conjugates with N-acetylglucosamine. Their formation from ursodeoxycholic acid was definitely demonstrated by 13C-labeling after giving [24-13C]ursodeoxycholic acid to one of the healthy subjects and to a patient with extrahepatic cholestasis in whom hydroxylation of ursodeoxycholic acid at C-23 was also observed. The patient was also found to excrete the double conjugate of ursodeoxycholic acid with N-acetylglucosamine and taurine. The N-acetylglucosaminidation of ursodeoxycholic acid in vivo was shown to occur at C-7.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylglucosamine↗
PubMed1993

Isolation of a human biliary glycoprotein inhibitor of cholesterol crystallization.

BACKGROUND: About 50% of populations in developed countries have bile supersaturated with cholesterol, which is a major risk factor for cholesterol gallstone formation. Despite the prevalence of supersaturated bile, only about 10% of these populations develop gallstones. The existence of a biliary protein that inhibits cholesterol crystallization was hypothesized to explain this discrepancy. This report outlines the purification and characterization of such a human biliary glycoprotein. METHODS: Chromatographic methods were used for separation and characterization. Additional steps included activity analysis by crystal growth assay, electrophoresis, and deglycosylation. RESULTS: The glycoprotein consists of a heterodimer, M(r) of 120 kilodalton, with subunits of M(r) of 63 kilodalton and 58 kilodalton. Each of the subunits is characterized by an isoelectric point of 6.6 and shows comparable inhibitory activity. Deglycosylation of the subunits show that they share a similar polypeptide backbone (M(r) of 35 kilodalton) based upon a highly similar amino acid profile. This suggests that differential subunit glycosylation alone may account for the apparent heterodimeric structure. CONCLUSIONS: No other human biliary glycoprotein has been found thus far that shows cholesterol crystal growth-inhibiting activity. Thus, it may be of importance in preventing gallstone formation in healthy populations.

Amino Acids↗
PubMed1991

Biotransformation study of para-substituted phenylpiperazines in beagle dogs by gas chromatography-mass spectrometry.

1. Beagle dogs were treated orally (10 mg/kg) with para-chloro-, para-fluoro- and para-methyl-phenylpiperazine derivatives, and urine was collected for 72 h after treatment. 2. Metabolites were extracted, converted into trimethylsilyl (TMS) derivatives and examined by g.l.c.-mass spectrometry. 3. The metabolites fall into two main groups, N-desphenylated metabolites, which result from N-desphenylation, and N-phenyl metabolites. 4. Two kinds of hydroxylated metabolites were found. Some lost the original para substituent (Cl, F or CH3); others retained it. 5. These results are consistent with the NIH shift reaction.

Animals↗
PubMed1991

Inhibition and promotion of cholesterol crystallization by protein fractions from normal human gallbladder bile.

Pooled, normal human gallbladder biles were initially separated on a molecular sieving chromatography column to remove soluble mucin glycoproteins as well as high molecular weight proteins (greater than 200,000). The remaining lower molecular weight proteins and other bile components were then examined by lectin affinity chromatography with four different types of lectin. The separated bound fractions were compared for inhibiting and promoting activities with a newly devised sensitive cholesterol crystal growth assay and for differences in electrophoretic patterns on SDS-gels. Protein factors (presumably glycoproteins) were found to have both inhibiting and promoting activities, even in the absence of cholesterol gallstone disease. The promoting effect was indicated by shortened crystal detection times and increases in crystal growth rate; whereas the inhibiting effect was indicated by decreases in crystal growth rate and reductions in the final crystal concentration as determined by the growth assay. Affinity chromatography mitigated the major problems of removing both lipids and pigment from the glycoproteins. In addition, partial purification of bound fractions with potent cholesterol crystal nucleation-altering activity can be obtained by this technique.

Anticholesteremic Agents↗
PubMed1991

Hepatic extraction of organic anions in the rat depends on ligand hydrophobicity.

Non-bile-salt cholephilic organic anions are efficiently taken up by the liver. Recent work from our group has suggested the possible importance of relative hydrophobicity among various organic anions in hepatic uptake. To further validate and clarify this, we studied hepatic extraction of five different cholephilic dyes using the isolated perfused rat liver in single-pass mode. Albumin binding affinities and capacities for each of the ligands were measured in vitro to permit evaluation of in vivo interactions for each of them over a spectrum of unbound ligand concentrations. As expected, a strong positive correlation was found between ligand hydrophobicity and the relative degree of albumin binding affinity and capacity. Using appropriate experimental conditions, we also found a strong positive correlation between hepatic extraction efficiency for a given ligand and both its hydrophobicity and its unbound concentration. These data indicate that where the unbound ligand concentration is significant, the greater the ligand hydrophobicity, the greater is its efficiency of hepatic extraction. We conclude that hepatic extraction efficiency for non-bile-salt cholephilic organic anions depends on a combination of ligand hydrophilic/hydrophobic balance and the availability of the unbound ligand for uptake.

Animals↗
PubMed1991

Nucleation and growth of cholesterol crystals. Kinetic determinants in supersaturated native bile.

Among the factors affecting the stability of supersaturated bile that culminates in the nucleation and growth of cholesterol crystals are biliary lipids. The abundance and composition of these lipids affect the composition of biliary vesicles that, if rich in cholesterol, are themselves unstable and that constitute precursor particles from which cholesterol crystals somehow arise. Kinetic factors can affect stability in either of two ways: They can inhibit cholesterol crystallization, thus stabilizing the system, or they can promote the process of cholesterol crystal nucleation, thus stabilizing the system.

Bile↗
PubMed1990

A sensitive method for determination of cholesterol growth using model solutions of supersaturated bile.

We describe a novel, facile, and highly reproducible spectrophotometric technique to measure a cholesterol crystal growth curve. This method permits a quantitative estimate of the potency or comparative abundance of a given kinetic effector substance. In addition to several internal validation procedures, data are provided that support the usefulness of the technique in the assay of substances with either known promoting activity, i.e., human mucin glycoprotein, or those with known inhibitory activity, i.e., human apolipoprotein A-I.

Apolipoprotein A-I↗
PubMed1990

Crystal growth-inhibiting proteins in bile.

The idea that biliary proteins somehow inhibit nucleation/crystal growth of cholesterol crystals in supersaturated human biles is not new, and some supportive, albeit preliminary, evidence has already been provided for this. Progress in purification of biliary effector proteins has been slow and hindered by the lack of a sensitive and convenient assay method. The formidable problems of removing large amounts of both mucin and lipids from the samples before isolation of biliary proteins has constituted another major obstacle. Recently, the combination of a newly developed nucleation and crystal growth assay and the systematic use of lectin affinity chromatography has enabled rapid progress to be made. With these approaches, glycoprotein fractions containing primarily inhibiting activity and other fractions containing primarily promoting activity have been isolated from normal human biles. Thus these opposing activities can coexist and influence a balance of effects potentially defining the presence of health or disease. The most recent studies have led to the isolation of a single glycoprotein having an extremely potent crystal growth-inhibiting activity.

Bile↗
PubMed1986

Effect of methylated bepridil on slow action potentials in cardiac muscle and vascular smooth muscle.

The anti-anginal agent bepridil blocks slow Ca2+ channels in a variety of tissues. Since bepridil accumulates inside cells, the possibility exists that bepridil acts, at least partially, from inside the cell. To test this possibility, we examined the effects of a quaternary ammonium analog of bepridil, methylated bepridil, which presumably would enter the cells less readily, on the Ca2+-dependent slow action potentials of guinea pig papillary muscles (in 25 mM [K+]0) and rabbit pulmonary arteries (in tetraethylammonium chloride). In cardiac muscle, methylated bepridil had little effect on the slow action potentials at low stimulation frequencies (0.5 Hz), but at higher frequencies (1.0 and 2.0 Hz) the slow action potentials were depressed and/or the muscle was unable to follow each stimulation. These effects are similar to those obtained with bepridil, but bepridil was more potent than methylated bepridil. In vascular smooth muscle cells, methylated bepridil inhibited the slow action potentials at a somewhat lower dose than bepridil. We conclude that, in cardiac muscle, bepridil probably has two sites of action, one outside the cell (presumably on or associated with the slow Ca2+ channel) and a second site inside the cell. On the other hand, in vascular smooth muscle cells, bepridil may act only on an external site.

Action Potentials↗
PubMed1982

Computer modeling of tumor hyperthermia (a dynamic lumped parameter model).

The thermal behavior of normal and neoplastic tissue is modeled by a set of coupled ordinary differential equations. The equations lump the tissue and tumor into individual compartments, so that the equations are time dependent. These equations represent an initial step in the development of a comprehensive model which may be used in studying the dynamics and control of the system under normo- and hyperthermic conditions.

Computers↗
PubMed1979

[Derivatives of 2,3,4,5,-tetrahydro-1H-pyrido-(3,2-b)azepine and 2,3,4,5-tetrahydro-1H-pyrido(2,3-b)azepine and their corresponding lactams. II. Synthesis and pharmacologic study of their psychotropic activity].

Preparation of the N-(2-diethylaminoethyl) derivatives of lactam (II) and of the N-(3-dimethylaminopropyl) derivative of lactam (XI) is described. Synthesis of the N-[4-(2-hydroxyethyl)piperazinylacetyl]- and 1-carbothiamide derivatives of azepine (I) and of the n-(chloroformyl)- and N-(carbamoyl) derivatives of azepine (XII) are also described. Some pharmacological results indicate a partial tranquilizing activity.

Animals↗
PubMedDate not supplied

Comparative study of the biotransformation of bepridil analogs in isolated liver cells from one rat. Relationships between structure and in vitro liver toxicity.

The biotransformation of several analogs of the anti-calcium agent bepridil was studied comparatively in liver cells isolated from one rat. Three types of metabolites were identified by mass spectrometry, resulting from three phase I reactions: hydroxylation, N-debenzylation and pyrrolidine ring opening. The amount of each bepridil analog untransformed after 18 h of incubation depended on its liver toxicity rather than on its concentration in the culture medium. The proportion of phase I metabolites identified remained constant regardless of toxicity. The difference delta c (in %) between the initial concentration of the analog tested and the sum of the concentrations of untransformed material and of identified metabolites decreased with the increasing hepatocyte toxicity. The analogs tested were responsible for the liver toxicity. The presence of substituents in different positions on the N-phenyl moiety increased liver toxicity; ortho-substituted analogs were more toxic than para- or meta-substituted ones.

Animals↗