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Biomedical subjects

I Witte

Publications and source records attributed to I Witte.

35 records · Page 2Linked to original sources
PubMed1991

The induction of DNA strand breaks and formation of semiquinone radicals by metabolites of 2,4,5-trichlorophenol.

The industrial pollutant 2,4,5-trichlorophenol (2,4,5-TCP) was metabolized with postmitochondrial liver fraction from Aroclor-1254 induced rats. The generated metabolites induced single strand breaks in PM2 DNA. Among the metabolites produced are the 3,4,6-trichlorocatechol (TCC) and the 2,5-dichlorohydro-quinone (DCH), whereby the induction of DNA scission by DCH was approximately one hundred times greater than that of TCC. In the 2,4,5-TCP metabolization mixture radicals were observed by ESR. They were identified as the semiquinones of TCC and DCH. ESR studies confirmed that both TCC and DCH autoxidize in aqueous solution to their semiquinone radicals. The involvement of reactive oxygen species in the DNA strand scission was demonstrated by using DMSO, SOD, and catalase as scavengers. Inhibition of strand breaks with the scavenger enzymes did not give homogeneous results for DCH and TCC. This indicated that the directly damaging species might be different for DCH and TCC.

Animals↗
PubMed1990

Comparison of the cytotoxicity and DNA-damaging properties of 2,4-D and U 46 D fluid (dimethylammonium salt of 2,4-D).

U 46 D Fluid (the dimethylammonium salt of 2,4-dichlorophenoxyacetic acid in a commercial formulation) was more toxic to human fibroblasts than 2,4-dichlorophenoxyacetic acid (2,4-D). Moreover, U 46 D Fluid induced single-strand breaks at apurinic/apyrimidinic (AP) sites of heat-acid treated PM2 DNA while 2,4-D did not. The 1H-NMR spectrum of the dimethylammonium (DMA) salt of 2,4-D indicated the formation of a complex via a six-membered aggregate of the DMA ion and the acid group of 2,4-D. The role of complex formation of the DMA salt of 2,4-D as a cause of single-strand breaking activity and increased cytotoxicity is discussed.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1990

The role of hydroxyl radicals in tetrachlorohydroquinone induced DNA strand break formation in PM2 DNA and human fibroblasts.

Tetrachlorohydroquinone (TCHQ), which has previously been identified as a metabolite of pentachlorophenol, induces DNA strand breaks in isolated DNA and in human fibroblasts. Strand break formation in PM2 DNA is prevented by the addition of catalase and the hydroxyl radical scavengers DMSO, ethanol and mannitol, whereas addition of SOD reduced SSB only slightly. Oxygen radicals are formed by the autoxidation of TCHQ to the tetrachlorosemiquinone radical. Desferrioxamine (0.2 mM) completely abolished strand break formation, whereas the metal chelator DETAPAC (1 mM) reduced SSB by only 8.5%. The formation of the semiquinone radical at physiological conditions is shown by ESR spectroscopy. Exposure of human fibroblasts to TCHQ also leads to DNA single strand breaks measured by the alkaline elution assay. These were reduced by addition of 5% DMSO. This indicates that at least part of the strand break formation in human cells is also due to the action of hydroxyl radicals.

Cells, Cultured↗
PubMed1990

Determination of regional blood flow in abdominal organs and other structures in normal female rats and in rats with TAA-induced chronic liver injury using 99mTc labelled HSA-microsphere technique.

A method for simultaneous determination of cardiac output and regional blood flow distribution in a chronically instrumented, unrestrained rat preparation for different experimental conditions (i.e. conscious, free movement; general anesthesia) and in an experimental chronic liver injury model is described. The use of a modified radioactive microsphere reference sample method using 99mTc labelled HSA-microspheres provides valid measurements of cardiac output [255 +/- 21.6 ml/(min.kg b.wt.)] and of the determined blood flow rates of abdominal organs (with separate determination of arterial and portal-venous hepatic blood flow rates; the latter by means of arterial blood flow measurement of the gastrointestinal tract and the spleen), the myocard, the adrenals, the kidneys, and various brain regions. Furthermore, it is demonstrated that this measuring approach with chronical preparation can also advantageously be used in pharmacological or pathogenetical studies, especially because of the simple measuring equipment and the comparatively low costs that offer a broader application.

Abdomen↗
PubMed1989

The in vitro metabolites of 2,4,6-trichlorophenol and their DNA strand breaking properties.

The carcinogenic compound 2,4,6-trichlorophenol (2,4,6-TCP) was incubated with rat liver S-9 fraction. Three metabolites were identified: 2,6-dichloro-1,4-hydroquinone (DHQ), and two isomers of hydroxypentachlorodiphenyl ether (OH-Cl5-DPE). The latter are probably products of microsomal .OH radical attack on the trichlorophenol molecule forming phenoxy free radicals. These would undergo dimerizations with other molecules present in solution. The 2,6-dichloro-1,4-semiquinone free radical was identified by ESR spectroscopy. It is formed at physiological conditions in phosphate buffer at pH 7.2 and 7.8, with a more intensive signal at the more alkaline pH. The formation is probably due to the autoxidation of the corresponding hydroquinone. Incubation of a mixture of metabolites with PM2 DNA at pH 7.2 resulted in single strand breaks. Addition of catalase and dimethylsulfoxide (DMSO) inhibited the DNA strand scission. It was concluded that reactive oxygen species (ROS), produced during the formation of the semiquinone radical, were responsible for the observed DNA damage. The significance of the ROS and the semiquinone free radical is discussed in view of the reported tumorgenicity of 2,4,6-TCP in rats and mice.

Animals↗
PubMed1980

Correlation of the colony-forming abilities of xeroderma pigmentosum fibroblasts with repair-specific DNA incision reactions catalyzed by cell-free extracts.

Several normal and XP group A fiblast cell lines were exposed to the weakly carcinogenic and toxic agent methyl methanesulfonate, and the differences in their abilities to form colonies were determined. The XP group A cell lines investigated exhibited higher sensitivity towards methyl methanesulfonate than normal cell lines. Correspondingly, cell-free extracts of the same XP cell lines differed from normal ones in cleaving methyl methane-sulfonate-treated double-stranded DNA less rapidly. Since depurinated DNA was cleaved by XP and normal cell lines at equal rates, it was concluded that the differences observed with methylated DNA were due to a reaction preceding cleavage at apurinic sites. In control experiments using extracts from Chinese hamster ovary cells liberation of m3Ade was observed indicating the presence of 3-methyl-adenine DNA glycosylase activity. Furthermore, extracts from a normal fibroblast line liberated small amounts of m3Ade, whereas the one of a XP group A cell line was found to be less effective. The possible role of 3-methyl-adenine DNA glycosylase activity as a rate-limiting factor in the incision step has been discussed.

Bacteriophages↗
PubMedDate not supplied

DNA-damaging properties and cytotoxicity in human fibroblasts of tetrachlorohydroquinone, a pentachlorophenol metabolite.

The DNA-damaging potential of pentachlorophenol (PCP) and its metabolite tetrachlorohydroquinone (TCH) was investigated. TCH was found to bind covalently to calf-thymus DNA and to cause single-strand breaks in PM2 DNA. No DNA-damaging effects were observed for PCP. Exposure of human fibroblasts to PCP and TCH showed that TCH is more toxic, when colony-forming ability after exposure to the agent is used as a measure of toxicity. In the evaluation of the mutagenic and carcinogenic potential of PCP the metabolite TCH should be taken into consideration.

Biotransformation↗