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Biomedical subjects

K J Freundt

Publications and source records attributed to K J Freundt.

At least 37 records · Page 2Linked to original sources
PubMed1983

Blood acetaldehyde levels in alcohol-dosed rats after treatment with ANIT, ANTU, dithiocarbamate derivatives, or cyanamide.

In adult female Wistar rats, pretreated by gavage with two doses - 16 or 256 mumol/kg - of cyanamide, TMTD (tetramethylthiuram disulfide), TMTM (tetramethylthiuram monosulfide), Ziram or Zineb at 90 min or 18 h before administration of 2 g of ethanol/kg i.p., the blood acetaldehyde levels were significantly increased for 90 - 240 min after ethanol administration (exceptions were noted after exposure to Zineb for 90 min or to low-dosed cyanamide for 18 h). After pretreatment for identical periods with ANTU (N-1-naphthylthiourea) or ANIT (1-naphthylisothiocyanate) at doses extending into the LD50 range, the blood acetaldehyde levels of rats given the same dose of ethanol remained uninfluenced. The increase in blood acetaldehyde recorded after 16 mumol/kg p.o. of TMTM and TMTD remained detectable for up to 48 h. Onset of the cyanamide action occurred already after 45 min. While recognizing that results from animal experiments cannot be transposed without restriction to the human situation, it is concluded that occupational contacts with ANTU or ANIT are not likely to elicit increased blood acetaldehyde levels in man after ingestion of alcohol. The risk of an ethanol intolerance reaction due to a rise in blood acetaldehyde therefore does not appear to be warranted. The present findings indicate, however, that exposure to TMTD, TMTM, Ziram, Zineb or cyanamide is associated with a definite health risk; because of the long persistence of these substances in the body, the risk exists for a long time post-exposure.

1-Naphthylisothiocyanate↗
PubMed1981

The inhibitory action of dithiocarbamates and carbon disulphide on malondialdehyde formation resulting from lipid peroxidation in rat liver microsomes.

The dithiocarbamates (DTCs) disulfiram, thiram, diethyldithiocarbamate and dimethyldithiocarbamate on the equimolar base inhibited to the same extent both the lipid peroxidation (LPO) induced by ascorbic acid (non-enzymatic) and that stimulated by an NADPH-regenerating system with CCl4 admixture (enzymatic). Lipid peroxidation measurements were made in terms of malondialdehyde (MDA) formation in rat liver microsomes, or in the 9000 X g supernatant. The inhibitory action of tetramethylthiuram monosulphide was considerably weaker. Carbon disulphide (CS2) inhibited the enzymatic and non-enzymatic stimulated microsomal LPO by 4 orders less than the DTCs. In parallel with the inhibition of MDA formation, oxidative destruction of microsomal cytochrome P-450 was delayed with increasing concentrations of the DTCs. A well-correlated, non-linear, semi-logarithmic relation was found for the concentration-activity relationship for all DTCs and CS2. As the DTCs inhibited LPO both in heat-denatured and freshly prepared microsomes, it can be deduced that the DTCs intervene in a non-enzymatic oxidation phase of the LPO. The DTC inhibitory action is attributed to a radical-trap mechanism since LPO that has already been initiated was inhibited with the DTCs. However, more inhibitor is required to trap the radicals the later the DTC administration takes place.

Animals↗
PubMed1980

Fatty acids in hepatic microsomal and mitochondrial phospholipids.

Hepatic microsomal phospholipids of rats showed a high incorporation rats of the precursor palmitic acid (1-[14C]-labelled), in comparison to U-[14C]-glucose and 1-[14C]-glycerol and in contrast to their corresponding mitochondrial fractions. This depends on a predominant occurrence of palmitic acid close to stearic acid in the 1- and 2-position of the glyceride skeleton of phosphatidylcholine and phosphatidylethanolamine, respectively. The reported results provide new approaches to the investigation of drug-induced interactions at the microsomal target on the molecular level, especially to establish sensitive criteria for drug-induced effects.

Animals↗
PubMed1979

Production of endogenous D-glucaric acid and oxidative N-demethylation of amidopyrine in man: lack of correlation.

In adult male subjects there was no positive correlation between the 24-hr urinary excretion of D-glucaric acid (D-GA) and the metabolic formation of 4-aminoantipyrine (AAP) from amidopyrine. It is concluded that in man the urinary D-GA excretion rate cannot be regarded in general as an indirect measure of the activity of microsomal drug conversion by means of mixed-function oxidases (MFO). Normal urinary value for D-GA: 16.3 +/- 1.5 (mean +/- SEM) mumols saccharo-1,4-lactone/24 hr as equivalent.

Adult↗
PubMed1978

Inhibition of mixed function oxidases in rat liver by trans- and cis-1,2-dichloroethylene.

A single 8-h exposure to trans-1,2-dichloroethylene (t-DCE) or cis-1,2-dichloroethylene (c-DCE) at 200 ppm (hygienic standard in workplaces) resulted in a significant increase in the hexobarbital sleeping time, the zoxazolamine paralysis time, and the metabolic formation of 4-aminoantipyrine from aminopyrine in adult female Wistar rats. Higher DCE concentrations caused a dose-dependent and substantial enhancement of these effects, the effects of c-DCE being stronger than that of t-DCE. In the course of enzyme-kinetic measurements in isolated rat liver microsomes, t-DCE proved to be a competitive inhibitor of the oxidative N-demethylation of aminopyrine and of the O-demethylation of p-nitroanisole. It is concluded from the results that the inhibition of hepatic drug metabolism is caused by a competitive and reversible interaction of the 2 DCE isomers with the mixed-function oxidase system, the interaction possibly operating at the type I binding site.

Animals↗
PubMed1978

Nervous system responses to work - site chemicals - toxicological basis.

A number of materials which are applied in the chemical industry in the work environment are liable to produce injury to health, particularly neurotoxic disturbances, when absorbed by the organism. The effects exerted are determined by the anatomic-structural factors of the nervous system and the physico-chemical characteristics of a given neurotoxicant. Some of the materials to be considered exhibit pronounced affinities for certain structures and ganglion groups in the central or peripheral nervous system. This gives rise to specific patterns of morphologic or functional disturbances or lesions and ultimately leads to the development of different clinical symptoms which manifest themselves as distinct intoxication pictures characteristic of certain work-site chemicals. Currently available suggestions for a grouping of industrial neurotoxicants which is both systematic and convenient to handle for practical purposes take their bearing from the clinical and morphologic-structural features reported in the literature.

Binding Sites↗
PubMed1978

Variable inhibition of human hepatic drug metabolizing enzymes by disulfiram.

In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.

Adult↗
PubMed1977

[Health hazards due to industrial substances. A toxicologic environmental problem].

Work-site chemicals are substances which are employed in manufacturing industrial operations. Contact with such materials may present a hazard to health. Substantial hygienic significance is to be attached to the detection of such injurious potentials by experimental and theoretical toxicology. The preparation of toxicologic expertises on industrial materials presents many problems. The standard approach is to utilize scientific methods on the basis of defined experimental models and quantitative relationships. Judgment of the toxicologic relevance is guided by well-documented epidemiologic or experimental data and the study of case histories. After scientific validation the result is used in practice for setting threshold limit values (MAK's, MIK's) for occupational health purposes.

Environmental Exposure↗
PubMed1977

Toxicity studies on trans-1,2-dichloroethylene.

Trans-1,2-dichloroethylene (t-DCE), an industrial solvent, proved to be moderately toxic when studied in small laboratory animals. In adult female rats brief (8 h) and prolonged (8 h daily, on 5 consecutive days a week, for more than 16 weeks) inhalation of 200 ppm--the current TLV/MAC in various countries--produced histological evidence of slight to severe fatty degeneration of the liver lobules and Kupffer cells. In addition marked pulmonary hyperaemia and alveolar septal distention were noted. Fibrous swelling of the cardiac muscle (with striation) just barely maintained) and hyperaemia remained detectable for as long as 14 h post-exposure, but only occurred at 3000 ppm/8 h. A concentration of 1000 ppm/8 h was required to produce a fall in blood albumin, urea nitrogen, alkaline phosphatase activities and erythrocyte count. The cited concentrations failed to produce prenarcotic symptoms of narcosis (central nervous system (CNS) depression). The LD50 was found to be 6.0 ml/kg i.p. and 1.0 ml/kg p.o. for female rats, and 3.2 ml/kg i;p. for female mice. In some of the rats killed in these experiments the organ changes were found to be identical to those observed after inhalation.

Administration, Oral↗
PubMed1977

Behavior of blood acetaldehyde in alcohol-treated rats following administration of thiurams.

Single moderate doses of Na-dimethyldithiocarbamate and Na-diethyldithiocarbamate (thiocarb), respectively, did not influence the rate of elimination of ethanol i.p. in female rats, but there was a concurrent substantial increase in the blood acetaldehyde content. Tetramethylthiuram disulfide (thiram) produced a slight decrease in the rate of elimination of ethanol, while a comparable dose of tetramethylthiuram disulfide (disulfiram) failed to affect ethanol disappearance. At the same time, the blood acetaldehyde concentration showed a considerable increase which after thiram was much more significant than after disulfiram, Identical thiuram doses caused a significant reduction in the rate of elimination of acetaldehyde i.v., which suggests an inhibition of the aldehyde dehydrogenasel aldehyde oxidase and helps to explain the elevated blood acetaldehyde concentration which was observed in the presence of ethanol. It is concluded from these findings that thiuram activity decreases as the number of carbon atoms at the side-chains of the molecule is increasing.

Acetaldehyde↗
PubMed1976

[In vitro inhibition of oxidative N-demethylation with carbon disulfide].

Earlier findings have shown that in experimental animals (rat) and in man inhaled carbon disulphide (CS2) reversibly inhibits the non-specific oxidative drug metabolism caused by hepatic microsomal enzymes. Very little is known concerning the underlying mechanism. The present investigations were undertaken to throw light on this question. After addition of an NADPH-regenerating system to liver microsomes isolated from adult female Wistar rats, the oxidative N-demethylation of aminopyrine was measured under simultaneous exposure to CS2 by quantitatively determining the formaldehyde obtained; the resulting data were evaluated using enzyme-kinetic parameters according to Lineweaver-Burk: 1. Following acute exposure to low and medium-grade CS2 concentrations (20-400 ppm/8 h), the pattern of inhibition in rat liver microsomes is identical to that obtained in normal liver microsomes to which CS2 had been added. This finding seems to suggest that the inhibitory process under in vivo and in vitro conditions is based on one and the same molecular mechanism. 2. Upon addition of CS2 the in vitro pattern of inhibition corresponds to a strong mixed-type inhibition. 3. It is concluded from the enzyme-kinetic behaviour that CS2 attacks at two different sites of the enzyme molecule: Binding to the first site is followed by inhibition, as evidenced by the rise of Km; after saturation of this site, a second site is occupied resulting in a reactivation and, beyond this, an activation of enzyme output, as shown by the decrease of Km. CS2 exhibits a high affinity for the first site, and a low affinity for the second site. Binding at the first site is reversible. The possibility that the active centre in the enzyme molecule is the site where binding of the inhibitor occurs is ruled out. 4. A continuous decrease of Vmax at increasing inhibitor concentration is causally related with the formation of an enzyme/substrate inhibitor complex. 5. The CS2 added to the microsomes can be eliminated by helium gas; this is followed by the return of the original enzyme activity. It is concluded from this behaviour that under in vitro conditions CS2 itself (rather than its metabolites) acts as the inhibitor. 6. Oxygen treatment of the microsome-containing reaction mixture enhances the inhibition. In substrate-free control mixtures, addition of CS2 was followed by the dose-dependent formation of formaldehyde; a causal explanation is not readily available at this time.

Air Pollutants↗