Biomedical subjects

H Uehleke

Publications and source records attributed to H Uehleke.

At least 19 recordsLinked to original sources

PubMed1982

Inhibition of microsomal drug oxidations by aliphatic halohydrocarbons: correlation with vapour pressure.

1. The effects of 12 halogenated aliphatic compounds on microsomal N-dealkylation, C-hydroxylation and N-oxidation of N-methylaniline and N-hydroxylation of p-chloroaniline were determined in closed reaction vessels. 2. There is no correlation between the volatility of the agents investigated and their binding characteristics to oxidized or reduced microsomal cytochrome P-450. 3. High correlation was observed between inhibiton of cytochrome P-450-mediated drug oxidations and the boiling points (vapour pressure) of the individual compounds. The N-oxidation of N-methylaniline, which is not catalysed by cytochrome P-450, did not show this correlation. 4. Other factors e.g. ligand formation with reduced cytochrome P-450, lipid peroxidation and haem destruction, production of carbon monoxide, and alterations of microsomal cofactors, did not produce significant inhibition. 5. Many artefacts occur when reaction velocities, inhibition constants and optical affinities to microsomal cytochromes are determined for volatile chemicals under uncontrolled conditions.

Animals↗

PubMed1980

Trichloroethylene vapours do not produce dominant lethal mutations in male mice.

Exposure of male mice to trichloroethylene vapours during 24 h at levels or 50, 202 and 450 ppm did not reveal mutagenic effects in the dominant lethal assay. The following parameters were registered and evaluated: Fertilization rate, post-implantation loss, preemplantation loss and dominant lethal mutations.

Animals↗

PubMed1980

Basic requirements for long-term assays for carcinogenicity.

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Animals↗

PubMed1979

The effects of 2,2-diethylallylacetamide on hepatic cytochromes in rats and in vitro.

The application of 0.15 and 0.3% of diethylallylacetamide (DA) in the drinking water to rats during 10 days increased the relative liver weight, the yield of hepatic microsomes, and cytochromes P-450 and b5. Single s.c. doses of 400 mg DA per kg reduced cytochrome P-450 concentrations in the hepatic endoplasmic reticulum of rats. This effect was considerably more pronounced in rats pretreated with phenobarbital. The activity of 5-aminolaevulinic acid synthesis in liver mitochondria, and total liver porphyrins increased. In incubations of metabolizing hepatic microsomes from rabbits pretreated with phenobarbital 75% of 0.1 mM DA was degraded after 1 h. The aerobic incubation of 0.1 mM DA with rabbit hepatic microsomes in the presence of NADPH produced 50% destruction of cytochrome P-450 within 1 h. Addition of EDTA revealed that a part of this destruction cannot be explained by accelerated lipid peroxidation.

5-Aminolevulinate Synthetase↗

PubMed1978

Kinetics and metabolism of 2,2-diethylallylacetamide in dog and man.

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Acetamides↗

PubMed1977

Irreversible binding of 14C-labelled trichloroethylene to mice liver constituents in vivo and in vitro.

1. 14C-labelled trichloroethylene was injected i.p. into male mice (10 mumole/g of b.w.). The radioactivity irreversibly bound to hepatic protein reached highest levels after 6 h: 2 nmole/mg in cytosol protein, 4.4 nmole/mg in mitochondrial protein, and 7.6 nmole/mg in microsomal protein. 2. The commercial trichloroethylene contained radioactive impurities binding to proteins without metabolic activation. Purification by various extractions removed 60-70% of those materials. In aerobic incubates of mice hepatic microsomes and NADPH the covalent binding rate of the purified trichloroethylene was 1.4 nmole/mg protein in 60 min. The activity of rat liver microsomes was approximately 40% less. Covalent binding increased 2-fold with microsomes of mice pretreated with phenobarbital.

Animals↗

PubMed1977

Spectral evidence for 2,2,3-trichloro-oxirane formation during microsomal trichloroethylene oxidation.

During aerobic incubation of trichloroethylene with rabbit liver microsomes and NADPH a difference absorption peak appears at 451-452 nm. Trichloroethylene does not form a ligand absorption spectrum with hepatic microsomes reduced by dithionite, or in anaerobic incubates in the presence of NADPH. Addition of trichloroethylene epoxide (2,2,3-trichloro-oxirane) to reduced suspensions of rabbit liver microsomes produces high difference absorption at 452 nm, the optical Ks being approximately 2 mM. Of all possible metabolites of trichloroethylene only trichloroethanol forms absorption in the vicinity of 480 nm, and the broad absorption band reveals relatively low absorption near 450 nm. Dichloroacetyl chloride is the main thermal rearrangement product of trichloroethylene epoxide, and also produces 452 nm absorption in reduced microsomes. However, the difference absorption is 5 times smaller than the absorption produced by the intermediate formed during incubation of trichloroethylene in metabolising liver microsomes. These observations include strong evidence for epoxide formation during microsomal oxidation of trichloroethylene. 14C-labelled trichloroethylene binds irreversibly to hepatic macromolecules in vivo and in vitro. Possible rearrangement pathways of 2,2,3-trichloro-oxirane and reactive intermediates are presented.

Animals↗

PubMed1977

Irreversible binding of 3-14C-antipyrine to hepatic protein in vivo and in metabolizing liver microsomes.

After i.p. injection of 3-14C-antipyrine (10 micronmole = 1.9 mg with 10 micronCi per 10 g of body weight) to mice radioactivity was irreversibly bound to liver proteins. The irreversible binding reached maximal values of 0.15 nmole/mg protein in liver microsomes after 30-60 min. During 60 min incubation with liver microsomes of mice and rabbits (phenobarbital pretreated) and a NAKPH-regenerating system 3-14C-antipyrine was irreversibly bound to microsomal protein at a rate of 1.5 nmole/mg protein (mouse) and 3 nmole/mg protein (rabbit). In identical incubates with rabbit liver microsomes the 4-hydroxylation of antipyrine was 24 nmole/mg protein in 60 min and formaldehyde production from antipyrine 3 nmole/mg protein in 60 min. In incubates with rabbit liver microsomes the binding rate was 80-90% inhibited by 1mM metyrapone, SKF 525-A and trichloropropene epoxide respectively; 4-hydroxylation was 70-80% inhibited by the same substances. In the presence of 1mM GSH, cysteine or ethylene diamine binding was 30-40% inhibited, whereas 4-hydroxylation showed no inhibition.

Agranulocytosis↗

PubMed1977

Metabolic activation of haloalkanes and tests in vitro for mutagenicity.

1. During incubation of 14CCl4, 14CHCl3, [14C]halothane, or 14CCl3F with liver microsomes and NADPH, considerable radioactivity is bound irreversibly to endoplasmic protein and lipid. However, no 14C was detected in the ribosomal RNA. 2. None of the four haloalkanes studied induced mutations after incubation with liver microsomes and the bacterial tester strains S. typhimurium TA 1535 and TA 1538. 3. Very low or no activity was associated with soluble protein or RNA added to incubation mixtures of the four haloalkanes with liver microsomes.

Animals↗

PubMed1975

A comparative study on the irreversible binding of labeled halothane trichlorofluoromethane, chloroform, and carbon tetrachloride to hepatic protein and lipids in vitro and in vivo.

1) After intraperitoneal injection of labeled CCl4, CHCl3, and halothane in mice, 14C is preferentially bound to liver endoplasmic protein and lipid. A considerable activity is also associated with mitochondrial constituents. Maximal protein binding (nmol/mg): CCl4: 2.8 (0.5 hrs); CHCl3: 11.5 (6 hrs); halothane: 5 (6 hrs). Lipid binding: CCl4: 6.4 (5 min); CHCl3: 8 (4 hrs); halothane: 13.5 (2 hrs). The form of the binding curves in microsomal and mitochondrial protein and lipid differed with the individual haloalkanes. 2) The irreversible (covalent) binding of 14C from labeled haloalkanes in anaerobic suspensions of isolated rabbit liver microsomes and NADPH after 30 min was for protein (lipid) (nmol/mg): CCl4: 15 (58); CHCl3: 3.4 (3.2); halothane: 2.3 (10); trichlorofluoromethane: 6.5 (30). Anerobic incubation favored dehalogenation, but CHCl3 metabolism and irreversible binding requires oxygen. The greatest differences in the in vitro "covalent" binding rates were observed with CHCl3 in rat, mouse, and rabbit. 3) Altered microsomal cytochrome P-450 concentrations in newborn animals, or produced by pretreatment of rats with phenobarbital, 3-methylcholanthrene (MC), or CoCl2 effected similar, but not proportional changes in the rates of irreversible protein and lipid binding. Upon addition of CCl4 the difference of light absorption of reduced liver microsomes from MC-pretreated rats containing cytochrome P-448 appeared at 452 nm. The irreversible binding rate in these microsomes was also increased. The small accleration in irreversible binding in liver microsomes from rats pretreated with isopropanol is not proportional to the high increase of CCl4 toxicity. 4) Practically no binding to added, soluble albumin or RNA was observed in microsomal incubates. However, 14C is bound to the nicotine-adenine dinucleotides of the NADPH system. All haloalkanes produced a similar increase of NADPH oxidation in incubates of rabbit liver microsomes and NADPH.

1-Propanol↗

PubMed1974