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Biomedical subjects

K H Summer

Publications and source records attributed to K H Summer.

At least 37 records · Page 2Linked to original sources
PubMed1989

Mutagenicity and cytotoxicity of 2-chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells.

The genotoxicity of the sensory irritant 2-chlorobenzylidene malonitrile (CS) to V79 Chinese hamster cells was investigated using the induction of gene mutations, micronuclei and DNA repair synthesis as biological endpoints. CS efficiently induced micronuclei and mutants resistant to 6-thioguanine in these cells, but it did not elicit DNA repair synthesis. Induction of micronuclei and mutants showed very similar courses of concentration dependence, suggesting that both events were caused by the same mechanism. The hydrolysis products of CS, o-chlorobenzaldehyde and malononitrile dit not induce micronuclei and were much less cytotoxic than CS. The observation of heritable genetic changes in cells exposed to CS in the absence of detectable DNA damage suggests that the genetic effects of CS are not caused by an interaction of the compound or its hydrolysis products with DNA. It appears more likely that the mutagenic activity is the consequence of effects of CS on the mitotic apparatus of the cells causing chromosomal aneuploidy.

Animals↗
PubMed1989

2,3,7,8, tetrachlorodibenzo-p-dioxin induces oxygen activation associated with cell respiration.

We have investigated the influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on bioenergetic functions of isolated heart-mitochondria. Electron transfer and energy conservation activities were found to be decreased in the presence of very low amounts of the polychlorinated biphenyl compound (1.5 nmol/mg mitochondrial protein). The effect was greatest when substrates for complex I were used. In this case coupling of oxidative phosphorylation to respiration was drastically diminished, essentially at the expense of state 3 respiration, and P/O values were found around 2 instead of 3. Succinate-related energy conservation remained practically unaffected in the presence of TCDD, suggesting an interference of the toxic compound at coupling site I. SOD plus catalase were found to protect energy-linked respiration from the effect of dioxin indicating the involvement of superoxide radicals and H2O2 in the development of the observed phenomena. The present contribution provides experimental evidence on the formation of these oxygen species in the presence of TCDD. Furthermore, the site of action of TCDD is demonstrated and discussed in relation to the oxygen radical formation observed.

Animals↗
PubMed1989

Oxidative stress and inherited cataracts in mice.

To determine whether an unbalanced redox state might accompany the development of particular inherited mouse cataracts, the lenticular content of oxidized glutathione (GSSG) and the activity of superoxide dismutase (SOD) were chosen as markers. For wild-type lenses, an enhanced GSSG content could be observed in females as compared to males. Such a sex effect could not be detected for the SOD activity. In the mutants, GSSG content in cataractous lenses was found to be enhanced in 2 of 7 cases; the increases in other mutants were not significant. Changes of the SOD activity were even less consistent and only a random correlation of GSSG content and SOD activity with cataractogenesis could be deduced.

Animals↗
PubMed1988

2-Nitropropane induces DNA repair synthesis in rat hepatocytes in vitro and in vivo.

The genotoxicity of 2-nitropropane (2-NP) and 1-nitropropane (1-NP) was investigated by measuring the induction of DNA repair synthesis in rat liver cells in vitro and in vivo. 2-NP strongly induced DNA repair synthesis in both cases. When applied in vivo, 2-NP was considerably more effective in hepatocytes from males than in those from females. 1-NP was not active in vitro or in vivo. 2-NP and 1-NP did not induce repair in cell lines of extrahepatic origin derived from rat, mouse, hamster and man. The results are consistent with the reported carcinogenicity of 2-NP in rat liver and suggest that the formation of hepatocarcinomas by 2-NP is due to the generation of a genotoxic metabolite from 2-NP by liver-specific metabolism.

Alkanes↗
PubMed1988

Metallothionein gene expression in mouse tissues by D-penicillamine.

The effect of D-penicillamine on metallothionein mRNA accumulation was examined in mouse tissues by Northern and dot blot analysis. This drug was given as a single intraperitoneal dose of 250 mg/kg body weight and the metallothionein mRNA content of the tissues was measured 1, 4, 8 and 24 hours later. A detectable increase of mRNA was observed after 1 hour and maximal accumulation was seen after 4 hours in the liver, kidneys, lungs, brain and spleen, whereas in the heart the maximum occurred after 8 hours. In the liver metallothionein mRNA was increased 14.5-fold over the control and in the kidneys it was increased by a factor of 9.2. A significant increase was also seen in the lungs, where it was 10 fold. To determine whether the increase is due to new transcription of the metallothionein gene, animals were pretreated with actinomycin D (1.0 mg/kg body weight) before receiving D-penicillamine. Actinomycin D prevented some of the D-penicillamine-induced increase in metallothionein mRNA, indicating that the drug, to some extent, acts at the transcriptional level. Regulation of metallothionein gene expression may play an important role in the molecular mechanisms involved in the clinical action of D-penicillamine in rheumatoid arthritis.

Animals↗
PubMed1988

Metallothionein in human liver and kidney: relationship to age, sex, diseases and tobacco and alcohol use.

The content of metallothionein (MT) was determined in the livers (MT-L) and the kidneys (MT-K) of 145 deceased persons. The individual values showed marked variations; average levels (arithmetic means +/- S.D.) were 154.9 +/- 151.4 mg/kg liver wet wt. and 160.5 +/- 150.4 mg/kg total kidney wet wt. In contrast to MT-L, MT-K increased with age up to a maximum around mid-life and decreased at higher ages. Neither the MT-L nor the MT-K depend on sex. The MT content significantly correlates with the macroscopic and histopathologic status of the liver. As compared to normal tissue, livers with fatty degeneration, cirrhosis and brown atrophy show MT-L values of 40%, 25% and 233% respectively. Low MT-L of 40% of the control values are also observed in individuals with a history of alcohol abuse. This decline preceded visible macroscopic pathological findings. MT-L also responds to the cause of death. At suicidal overdose of drugs the MT-L is lowered to 62% and at "mechanical" suicides it is increased to 137%. Whereas MT-K is essentially independent of the kidney status, it is significantly increased to approximately 190% in male smokers.

Adolescent↗
PubMed1987

Metallothionein-determination in biological materials: interlaboratory comparison of 5 current methods.

Five current methods of metallothionein (MT)-estimation in biological materials (Hg/TCA-, Cd/heme-, SH-assay, G 75-method and RIA) were compared. Uniform calibration was ensured by measuring the nitrogen-content of the standard-apoprotein after "Kjeldahl-digestion". Known amounts of rabbit standard Cd-MT I were recovered from identical rat S9-samples. In an overall rating, RIA and Cd/heme-assay performed best, whereas the other methods either underestimated (SH-, G 75) or overestimated (Hg/TCA) the 100%-expectation.

Animals↗
PubMed1987

Metallothionein, cadmium, copper and zinc levels of human and rat tissues.

Metallothionein (MT), zinc (Zn), copper (Cu) and cadmium (Cd) were determined in 10 tissues (brain, heart, kidney cortex, liver, lung, muscle, pancreas, small intestine, spleen and stomach) from human autopsies (10 male individuals, mean age 43 +/- 9 years, all smokers) and Wistar rats. The mean tissue concentrations of MT in the human samples varied between 3.8 and 495 micrograms/g wet weight in spleen and kidney cortex, respectively. In most tissues human MT levels were high as compared to rats; particularly in liver and kidney cortex human MT levels exceeded those of rats about 25- and 10-fold, respectively. Positive linear relationships were observed between Zn or Cu and MT in human liver and between Cd and MT in human kidney cortex.

Adult↗
PubMed1986

D-penicillamine induces rat hepatic metallothionein.

Intraperitoneal injection of D-Penicillamine (D-PA) at a dose range of 20-500 mg/kg increased rat hepatic but not renal and pancreatic metallothionein (MT). Elevated MT predominantly contained Zn. Maximal induction was obtained 18 h after a single injection of 200 mg D-PA/kg resulting in 148 +/- 18 micrograms MT/g liver which was 16.4-times the control level of 9 +/- 2 micrograms MT/g. At 48 h after injection, MT declined to 18 +/- 9 micrograms MT/g liver. At maximal MT increase the content of total hepatic Zn but not of Cu was elevated. Increased amounts of Zn in liver homogenate, cytosol and MT could be detected approximately 4 h after injection of 200 mg D-PA/kg. Concomitantly there was a decrease in Zn bound to cytosolic non-MT ligands. All Zn changes reversed at 18 h. These data show that already single doses of D-PA cause induction of Zn-thionein in rat liver and lead to synchronous redistribution of Zn from endogenous sources to newly synthesized MT.

Animals↗
PubMed1986

Determination of Cd-thionein in biological materials: comparative standard recovery by five current methods using protein nitrogen for standard calibration.

Five methods of metallothionein (MT) estimation in biological materials (Hg-saturation assay, Cd-saturation assay, thiolate group determination, Sephadex G-75 gel chromatography with subsequent Cd determination by Zeeman-AAS, and a radioimmunoassay (RIA) were compared for their ability to recover standard MT(rabbit Cd-MTI) from liver or kidney S9. Uniform molar calibration of all assays was achieved using the known amino acid composition of standard MT and the nitrogen content of the standard MT stock solution as measured after complete Kjeldahl digestion. Known molar amounts of standard MT were added exogenously to rat liver- or kidney-S9 samples and recoveries measured using the methods indicated. In an overall rating, RIA and Cd-saturation assay performed best with recoveries of 97 +/- 12.0 and 105 +/- 9.7%, respectively. On the other hand, the remaining methods either underestimated (thiolate group determination, G-75/Cd-AAS) or overestimated (Hg-saturation assay) the theoretical expectation by up to 44%.

Animals↗
PubMed1986

Isolation of glutathione-deficient mutants of the yeast Saccharomyces cerevisiae.

Glutathione-deficient (gsh-) mutants of the yeast Saccharomyces cerevisiae were isolated after UV treatment using MNNG as selective agent. For genetic and biochemical characterization 5 mutant strains were chosen which exhibited considerably decreased residual GSH contents varying from 2 to 6% of the wild-type levels. All 5 isolates showed a 2:2 segregation of the gsh-:GSH+ phenotypes alluding to a monogenic recessive mutation. Complementation analysis indicates that all gsh- mutants belong to one complementation group.

Fungal Proteins↗
PubMed1986

Stability of metallothionein in gastric juice.

Metallothionein (MT), is presumably the major Cd-binding component of human food. It is not or only partially destroyed by cooking. To study whether MT is stable in gastric juice MT was incubated at various pH values with pepsin and human gastric juice in vitro. Above pH 3.5 nearly all Cd remained bound to the protein and Cd-MT was resistant towards proteolysis. At pH values of 2.5 and 1.7 the protein was digested to 80% and 100%, respectively. At pH 2.5 two Cd-containing peptides with 25-30 amino acids similar to the alpha-domain of the protein were detected. At pH 1.7 these fragments were further degraded to smaller peptides. The results indicate that the pH-dependent proteolytic degradation of Cd-MT depends on the metal content of the protein. Furthermore, the identical results obtained with pepsin and human gastric juice suggest that Cd-MT proteolysis occurs in vivo and will affect Cd resorption.

Amino Acids↗
PubMed1986

Metallothionein and cadmium in human kidney cortex: influence of smoking.

Post-mortem specimens of human kidney cortex of 47 individuals classified according to their smoking habits were analysed for tissue cadmium and cadmium bound to metallothionein. The cadmium content in the kidney cortex of all individuals was 5-99 micrograms/g wet wt. In smokers consuming more than 20 cigarettes/day the mean content of renal cortex cadmium was twice that of non-smokers and amounted to 33.3 +/- 12.5 micrograms/g wet wt. The amount of cadmium bound to metallothionein of all individuals was 0.3-66 micrograms/g wet wt. directly correlating with the cadmium content of the kidney cortex (r = 0.932). More than 50% of renal cortex cadmium was associated with the metallothionein fractions. Due to constant values of zinc and copper in metallothionein the relative amount of zinc and copper to cadmium in metallothionein decreased with increasing tissue cadmium. Together with the elevated binding of cadmium to renal cortex metallothionein, cadmium increasingly was bound to non-metallothionein ligands. These results suggest that, in the renal cortex of smokers with elevated cadmium, a major portion of cadmium is bound to metallothionein. However, it is unclear yet whether the binding of cadmium to metallothionein with subsequent liberation of the metal during degradation of the protein, the impairment of metallothionein functions by the binding of cadmium or the increased binding to non-metallothionein ligands contribute to the toxicity of cadmium in highly exposed individuals.

Adult↗
PubMed1985

Metallothionein content and zinc status in various tissues of rats treated with iodoacetic acid and zinc.

Metallothionein (MT) content was determined in 11 tissues of saline-treated rats, and 18 h after single IP injections of iodoacetic acid (IA, 15 and 30 mg/kg) or zinc sulfate (20 mg zinc/kg). Zinc increased MT content in eight tissues, being most effective in pancreas, liver, and small intestine. After IA, MT increased in liver, muscle, pancreas, and thymus, the highest amount being in liver. Increased levels of total tissue zinc were observed in those tissues which clearly responded to the treatments with elevated MT levels, such as liver, kidney, small intestine, and pancreas. MT induction by zinc in these tissues was associated with an accumulation of zinc not bound to MT. In the IA-treated rats non-MT zinc accumulated in liver and pancreas. It is concluded that induction of MT by zinc and in particular by organic chemicals such as IA without exogenously supplied metals interferes with zinc homeostasis and the physiological role of MT in liver and extrahepatic tissues of the rat.

Animals↗
PubMed1985

Low content of hepatic reduced glutathione in patients with Wilson's disease.

In five of six patients with symptomatic Wilson's disease (WD) with increased hepatic copper content, increased renal copper excretion, and decreased serum concentrations of ceruloplasmin, significantly low levels of hepatic reduced glutathione (GSH) were found. Three of these patients showed increased levels of oxidized glutathione which in part could account for the missing GSH. These changes may result from increased lipid peroxidation due to the rise of intracellular copper concentration. Furthermore, WD patients showed a 50% decrease in the activity of hepatic GSH S-transferases. From these results we conclude that the disturbance in the hepatic glutathione system of patients with symptomatic WD may contribute to the perpetuation of liver damage. These patients, additionally, may be predisposed to an increased sensitivity to drugs interacting with glutathione.

Adult↗
PubMed1984

Genetical and biochemical studies of a dominant cataract mutant in mice.

A spontaneous mutation causing a nuclear opacity of the lens of the eye was detected among (101 X C3H) F1 hybrid mice. The nuclear opacity, provisional gene symbol Nop, is inherited as a single autosomal dominant gene. Penetrance on the genetic background of the 101-strain is complete. Heterozygotes and homozygotes are viable and fertile. The amount of protein after centrifugation at 3000 g is reduced in the cataractous lens. After isoelectric focusing a band at pH 8.5 in the protein pattern is missing. The glutathione redox-state of the cataractous lens is also affected. The amount of oxidized glutathione relative to the total amount of glutathione is increased from 2.7 to 7.8% in the Nop/ + mutant (P less than 0.01). Enzyme activities connected with the glutathione redox-cycle (glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase) are not affected. The activities of some glycolytic enzymes, phosphoglycerate kinase, glyceraldehyde-phosphate dehydrogenase, phosphoglyceromutase and triosephosphate isomerase are reduced (P less than 0.05). However, the concentration of ATP in the cataractous lens is unchanged.

Animals↗