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W Dekant

Publications and source records attributed to W Dekant.

At least 73 records · Page 4Linked to original sources
PubMed1995

Increased incidence of renal cell tumors in a cohort of cardboard workers exposed to trichloroethene.

A retrospective cohort study was carried out in a cardboard factory in Germany to investigate the association between exposure to trichloroethene (TRI) and renal cell cancer. The study group consisted of 169 men who had been exposed to TRI for at least 1 year between 1956 and 1975. The average observation period was 34 years. By the closing day of the study (December 31, 1992) 50 members of the cohort had died, 16 from malignant neoplasms. In 2 out of these 16 cases, kidney cancer was the cause of death, which leads to a standard mortality ratio of 3.28 compared with the local population. Five workers had been diagnosed with kidney cancer: four with renal cell cancers and one with a urothelial cancer of the renal pelvis. The standardized incidence ratio compared with the data of the Danish cancer registry was 7.97 (95% CI: 2.59-18.59). After the end of the observation period, two additional kidney tumors (one renal cell and one urothelial cancer) were diagnosed in the study group. The control group consisted of 190 unexposed workers in the same plant. By the closing day of the study 52 members of this cohort had died, 16 from malignant neoplasms, but none from kidney cancer. No case of kidney cancer was diagnosed in the control group. The direct comparison of the incidence on renal cell cancer shows a statistically significant increased risk in the cohort of exposed workers. Hence, in all types of analysis the incidence of kidney cancer is statistically elevated among workers exposed to TRI.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Sex, organ and species specific bioactivation of chloromethane by cytochrome P4502E1.

1. In the male mouse, chloromethane produces renal tumours after inhalation, and tumours were not seen in the female mouse and in both sexes of rat exposed under identical conditions. 2. Cytochrome P4502E1 present in kidney microsomes from the male mouse oxidized chloromethane to formaldehyde, and the amount of formaldehyde formed was dependent on the hormonal status of the animals and correlated well with the ability of the microsomes to oxidize chlorzoxazone, a specific substrate for cytochrome P4502E1. In kidney microsomes from the female mouse, significantly lower rates of oxidation of chloromethane and chlorzoxazone were observed; oxidation could be induced by testosterone pretreatment of the female. 3. In liver microsomes from both sexes of mouse, the rates of oxidation of chloromethane and chlorzoxazone were two-fold higher than in kidney microsomes from the male, however, no sex differences in the rates of oxidation were observed. 4. The rates of oxidation in mouse liver microsomes for both substrates could be markedly increased by pretreatment with the cytochrome P4502E1 inducer ethanol. 5. Kidney microsomes from both sexes of rat did not catalyze the formation of detectable concentrations of formaldehyde from chloromethane and exhibited only low rates of chlorzoxazone oxidation; in liver microsomes of both sexes of rat an ethanol-inducible oxidation of chloromethane and chlorzoxazone was observed.

Animals↗
PubMed1995

The role of cytochrome P4503A1/2 in the sex-specific sulfoxidation of the hexachlorobutadiene metabolite, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine in rats.

Hexachlorobuta-1,3-diene (HCBD) is a selective nephrotoxin and a potent nephrocarcinogen in rodents. Its toxicity and carcinogenicity is based on a multistep bioactivation pathway. Glutathione conjugation seems to be the only bioactivation pathway for HCBD leading to reactive intermediates, which are thought to be responsible for the observed nephrotoxic effects. Recent in vivo studies revealed a novel urinary metabolite in male, but not female, rats after administration of [14C]HCBD. This metabolite was identified as (E)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine-sulfoxide (N-Ac-PCBC-SO). The objective of this study was to elucidate the enzyme(s) involved in this particular oxidation and to find an explanation for the sex differences in the formation of N-Ac-PCBC-SO. Both cytochrome P450 and flavin-containing monooxygenases (FMO) may catalyze the oxidation of N-Ac-PCBC-SO. The use of various competitive and allosteric inhibitors of cytochrome P450 and FMO (i.e. metyrapone, N-benzylimidazole, thiobenzamide, CO, n-octylamine, and heat inactivation studies) showed that the sulfoxidation of (E)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)- L-cysteine is catalyzed by cytochrome P450 enzymes. In microsomes from male rats pretreated with pyridine, phenobarbital, and dexamethasone, an increase in the rates of sulfoxide formation was only seen in microsomes from dexamethasone- and phenobarbital-induced animals. Moreover, troleandomycin, a selective chemical inhibitor for enzymes of the cytochrome P4503A family, inhibited sulfoxide formation by > 80%. Correlation of sulfoxide formation with testosterone 6 beta-hydroxylation, a marker of cytochrome P4503A1/2 in the rat, underlined the finding that cytochrome P4503A is the predominant cytochrome P450 responsible for this particular oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1994

Aminoacylases.

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Amidohydrolases↗
PubMed1994

Role of P4502E1 in the metabolism of 1,1,2,2-tetrafluoro-1-(2,2,2-trifluoroethoxy)-ethane.

1. The metabolism of 1,1,2,2-tetrafluoro-1-(2,2,2-trifluoroethoxy)-ethane (HFE), a prospective chlorofluorocarbon alternative, was studied in rat and human liver microsomes and in rat in vivo. 2. HFE was metabolized to inorganic fluoride, trifluoroacetaldehyde hydrate, trifluoroacetic acid and difluoroacetic acid, which were identified by 19F-nmr in microsomal incubation. After i.p. dosing with 200 mg/kg HFE to rat, trifluoroacetic acid and trifluoroacetaldehyde hydrate were identified as urinary metabolites. 3. The formation of inorganic fluoride from HFE was used to quantify oxidative metabolism. In liver microsomes from untreated rat, formation of inorganic fluoride could not be detected. However, microsomes from rats treated with P4502E1 (2E1) inducers ethanol and pyridine catalysed the formation of fluoride at different rates. The extent of fluoride formation in microsomes correlated with the amount of 2E1 protein as determined by immunoblots with a polyclonal antibody and with the extent of oxidation of p-nitrophenol and chlorzoxazone, two specific substrates for 2E1. 4. In different samples of human liver microsomes, the formation of inorganic fluoride correlated well with the ability of the microsomes to oxidize chlorzoxazone and p-nitrophenol and the amount of 2E1 protein as determined by immunoblots. 5. The obtained results suggest that 2E1 plays a major role in the metabolism of HFE in rat and man.

Animals↗
PubMed1994

Metabolism of 1,1-dichloro-2,2,2-trifluoroethane in rats.

1. Chlorofluorohydrocarbons are presently being developed as alternatives for ozone-depleting chlorofluorocarbons. 1,1-Dichloro-2,2,2-trifluoro-[2-14C]-ethane (HCFC-123) is a chlorofluorohydrocarbon with potential widespread use and associated human exposure. As a part of the toxicological evaluation of HCFC-123, its metabolism was studied in rodents in a closed recirculating exposure system. 2. Two male rats were individually exposed for 6 h. Excretion of radioactivity was monitored for 48 h after the start of the exposure. Of the radioactivity introduced into the chamber, 14% was recovered in urine within the period of observation. Excretion of metabolites in the urine was very slow. 3. Trifluoroacetic acid was the major metabolite of HCFC-123 and N-trifluoroacetyl-2-aminoethanol and N-acetyl-S-(2,2-dichloro-1,1-difluoroethyl)-L-cysteine were identified as minor urinary metabolites of HCFC-123. 4. Forty-eight hours after the start of the exposure, covalent binding of radioactive metabolites to protein was highest in liver followed by kidney and lung. Covalent binding above background levels was not observed in pancreas and testis, the target organs of HCFC-123 tumourigenicity. 5. These results suggest that the biotransformation of HCFC-123 in rodents follows a pathway identical to those of the extensively studied structural analogue halothane.

Administration, Inhalation↗
PubMed1994

Comparative metabolism of the renal carcinogen 1,4-dichlorobenzene in rat: identification and quantitation of novel metabolites.

1. The metabolism of 1,4-dichlorobenzene has been studied in the male and female Fisher 344 rat over 72 h after oral administration of 14C-1,4-dichlorobenzene (900 mg = 96.8 microCi/kg). No covalent binding of radioactivity could be detected in samples of liver, kidney, lung and spleen. The major route of excretion was with urine accounting for 41.3% of the dose for male and 37.8% of the dose for female rat within 72 h after dosing. 2. Urinary metabolites of 1,4-dichlorobenzene were identified and quantified. The major metabolites identified in the urine of both the male and female rat, were the sulphate and glucuronide of 2,5-dichlorophenol. Minor amounts of 2,5-dichlorohydroquinone were excreted as an unidentified conjugate. 3. 2-(N-acetyl-cysteine-S-yl)-1,4-dichlorobenzene and 2-(N-acetyl-cysteine-S-yl)-2,3-dihydro-3-hydroxy-1,3-hydroxy-1,4-dich lorobenzen e were minor metabolites excreted in the urine of both sexes. 4. A novel biotransformation pathway for 1,4-dichlorobenzene may be postulated, leading to the urinary excretion of a mercapturic acid of chlorophenol. 5. No marked differences in the distribution and excretion of metabolites of 1,4-dichlorobenzene were observed between the male and female Fisher 344 rat.

Acetylcysteine↗
PubMed1993

Bioactivation of nephrotoxins and renal carcinogens by glutathione S-conjugate formation.

Evidence has been accumulating that several classes of compounds are converted by glutathione conjugate formation to toxic metabolites. The aim of this review is to summarize the current knowledge on the biosynthesis and toxicity of glutathione S-conjugates derived from halogenated alkenes, and hydroquinones and quinones. Different types of toxic glutathione conjugates have been identified in detail; (i) conjugates which are converted to toxic metabolites in an enzyme-catalyzed multistep mechanism and (ii) conjugates which serve as a transport form for toxic quinones will be discussed. The kidney is the main, with some compounds the exclusive, target organ for compounds metabolized by these pathways. Selective toxicity to the kidney is easily explained due to the capability of the kidney to accumulate intermediates formed by processing of S-conjugates and to bioactivate these intermediates to toxic metabolites. The influences of other factors participating in the renal susceptibility and influencing human risk assessment for these compounds are discussed.

Animals↗
PubMed1993

DNA adduct formation in Salmonella typhimurium, cultured liver cells and in Fischer 344 rats treated with o-tolyl phosphates and their metabolites.

2-Phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide is an electrophilic and a neurotoxic metabolite of o-tolyl phosphates. In a previous paper we reported that 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide is mutagenic in Salmonella typhimurium TA100 and forms DNA adducts in incubations with nucleotides, nucleosides and isolated DNA. In the present study we compare DNA adduct formation using 32P-post-labelling assays in 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide-treated bacteria (S.typhimurium TA100) and hepatoma cells with DNA adducts formed in liver, kidney, lung and heart of tri-o-tolyl phosphate-exposed Fischer 344 male rats. In both bacteria and hepatoma cells two DNA adducts could be detected after treatment with 2-phenoxy-4H-1,3,2-benzodioxaphosphorin 2-oxide. The minor adduct co-chromatographed with synthetic N3-(o-hydroxy-benzyl)deoxyuridine 3' monophosphate after postlabelling. The major DNA adduct was a cytidine adduct, most likely N3-(o-hydroxybenzyl)deoxycytidine 3' monophosphate. Male Fischer 344 rats were treated orally for 10 days with tri-o-tolyl phosphate (50 mg/kg/day) and DNA was isolated from liver, kidney, lung, heart, brain and testes 1, 4, 7 and 28 days after giving the last dose. Analysis by 32P-postlabelling revealed that two adducts were present in the DNA isolated from liver, kidney, lung and heart on the first day after giving the last dose; DNA adducts were not detected in the brain and testes. The adduct pattern after in vivo treatment with tri-o-tolyl phosphate was identical with that found in bacteria and hepatoma cells treated with 2-phenoxy-4H-1,3,2-benzo-dioxaphosphorin 2-oxide, the major adduct being N3-(o-hydroxybenzyl)deoxycytidine 3' monophosphate and the minor N3-(o-hydroxybenzyl)deoxyuridine 3' monophosphate. Both DNA adducts persisted in the lungs for the entire observation period, whereas in the kidney only the cytidine adduct could be detected 28 days after the last dose of tri-o-tolyl phosphate. In liver and heart the adducts were detectable only on the first day after completion of the treatment. The results indicate that in addition to the well established neurotoxicity, some o-tolyl phosphates may have a carcinogenic potential.

Animals↗
PubMed1993

Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans: implications for the risk of trichloroethene exposure.

Excretion of mercapturic acids in the urine is indicative of the formation of electrophiles in the metabolism of xenobiotics. The determination of these mercapturic acids thus may be a useful method to estimate the exposure. We identified the nephrotoxic and mutagenic mercapturic acids N-acetyl-S-(1,2-dichlorovinyl)-L- cysteine and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine in the urine of workers exposed to 1,1,2-trichloroethene. A method to quantify these mercapturic acids by gas chromatography-mass spectrometry-selected ion monitoring was developed and appreciable amounts (2.8-3.8 mumole/L were found in human urine samples. Because deacetylation determines notably the amount of the excreted mercapturic acids, the formation of the resulting cysteine S-conjugates was comparably measured in subcellular fractions of rodent and human kidneys; significant species differences in acylase activity were found. The formation of mutagenic and nephrotoxic metabolites during 1,1,2-trichloroethene metabolism mandates a revision of the risk assessment of trichloroethene exposure.

Acetylcysteine↗
PubMed1993

Glutathione-dependent bioactivation of xenobiotics.

Glutathione conjugation has been identified as an important detoxication reaction. However, in recent years several glutathione-dependent bioactivation reactions have been identified. Current knowledge on the mechanisms and the possible biological importance of these reactions are discussed. 1. Dichloromethane is metabolized by glutathione conjugation to formaldehyde via S-(chloromethyl)glutathione. Both compounds are reactive intermediates and may be responsible for the dichloromethane-induced tumorigenesis in sensitive species. 2. Vicinal dihaloalkanes are transformed by glutathione S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl)glutathione S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates formed. 3. Several polychlorinated alkenes are bioactivated in a complex, glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation followed by cleavage to the corresponding cysteine S-conjugates, and, after translocation to the kidney, metabolism by renal cysteine conjugate beta-lyase. Beta-Lyase-dependent metabolism of halovinyl cysteine S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular macromolecules is responsible for the observed toxicity of the parent compounds. 4. Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.

Amino Acid Sequence↗
PubMed1992

Events that precede and that follow S-(1,2-dichlorovinyl)-L-cysteine-induced release of mitochondrial Ca2+ and their association with cytotoxicity to renal cells.

Previous studies showed that S-(1,2-dichlorovinyl)-L-cysteine perturbs intracellular Ca2+ homeostasis [Vamvakas et al., Mol Pharmacol 38: 455-461, 1990]. The objective of the present study was to investigate the cellular events that precede and that follow S-(1,2-dichlorovinyl)-L-cysteine-induced mitochondrial Ca2+ release. In incubations with isolated kidney mitochondria, S-(1,2-dichlorovinyl)-L-cysteine-induced Ca2+ efflux is preceded by increased oxidation of mitochondrial pyridine nucleotides and is prevented by ATP, an inhibitor of the hydrolysis of pyridine nucleotides, and by meta-iodobenzylguanidine, an acceptor of ADP-ribose moieties. In LLC-PK1 cells, elevation in the cytosolic Ca2+ concentration is followed by a several-fold increase in DNA double-strand breaks which is attributed to the activation of Ca2+- and Mg(2+)-dependent endonucleases. The formation of DNA double-strand breaks is followed by increased poly(ADP-ribosylation) of nuclear proteins. S-(1,2-Dichlorovinyl)-L-cysteine-induced cytotoxicity in LLC-PK1 cells is blocked by chelation of cytosolic Ca2+ with Quin-2, by inhibition of DNA fragmentation with aurintricarboxylic acid and by inhibition of increased poly(ADP-ribosyl)transferase activity by 3-aminobenzamide. These findings indicate that S-(1,2-dichlorovinyl)-L-cysteine bioactivation in renal cells may initiate the following cascade of events: increased oxidation and hydrolysis of mitochondrial pyridine nucleotides resulting in the modification of mitochondrial membrane proteins by pyridine nucleotide-derived ADP-ribose moieties, followed by Ca2+ release. Elevated Ca2+ concentrations may activate Ca(2+)-dependent endonucleases, which leads to DNA fragmentation followed by increased poly(ADP-ribosylation) of nuclear proteins and, finally, cytotoxicity.

Adenine Nucleotides↗
PubMed1992

Glutathione depletion, lipid peroxidation, DNA double-strand breaks and the cytotoxicity of 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone in rat renal cortical cells.

The mechanisms involved in the cytotoxicity of 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone, a model compound for hydroquinone derived mercapturic acids, were investigated in rat renal proximal tubule cells. 2-Bromo-3-(N-acetylcystein-S-yl)hydroquinone induced a time- and concentration-dependent decrease in cell viability and in the levels of cellular glutathione. Antioxidants such as N,N'-diphenyl-p-phenylene diamine and ascorbic acid and the iron chelator desferrioxamine very efficiently protected the cells from 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone without influencing glutathione depletion. The acetoxymethyl ester of the Ca2+ chelator Quin-2, the inhibitor of the Ca(2+)- and Mg(2+)-dependent endonucleases, aurintricarboxylic acid and the poly(ADP-ribose)-polymerase inhibitor 3-aminobenzamide also ameliorated 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone cytotoxicity. Moreover, 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone depleted Ca2+ from isolated kidney mitochondria, increased the amount of malondialdehyde in rat kidney cells and induced DNA double-strand breaks in renal cells in culture. These results suggest that renal cells oxidize 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone to the corresponding quinone; this soft electrophile reacts rapidly with glutathione, thus depleting cellular glutathione concentrations as indicated by the tentative identification of a 2-bromo-3-(N-acetylcystein-S-yl)hydroquinone thioether in the incubation medium of renal cells treated with the mercapturate. As a result of the massive glutathione depletion, peroxidative mechanisms then cause an elevation of the cytosolic concentrations of ionized calcium; impairment of the ability of the mitochondria to sequester Ca2+ plays an important role in the elevation of the Ca2+ concentration. Finally, activation of Ca(2+)- and Mg(2+)-dependent endonucleases results in DNA damage and cell death.

Acetylcysteine↗
PubMed1992

p-aminophenol nephrotoxicity: biosynthesis of toxic glutathione conjugates.

p-Aminophenol causes necrosis of the pars recta of the proximal tubules in rats, and its nephrotoxicity may be due to glutathione-dependent bioactivation reactions. We have investigated the hepatic metabolism of p-aminophenol in Wistar rats and the cytotoxicity of formed glutathione S-conjugates in rat renal epithelial cells. After ip application of p-aminophenol (100 mg/kg), the following metabolites were identified in rat bile: 4-amino-2-(glutathion-S-yl)phenol, 4-amino-3-(glutathion-S-yl)-phenol, 4-amino-2,5-bis(glutathion-S-yl)phenol, 4-amino-2,3,5(or 6)-tris(glutathion-S-yl)phenol, an aminophenol conjugate (likely a sulfate or glucuronide), acetaminophen glucuronide, and 3-(glutathion-S-yl)acetaminophen. 4-Amino-3-(glutathion-S-yl)phenol, 4-amino-2,5-bis(glutathion-S-yl)phenol, and 4-amino-2,3,5(or 6)-tris(glutathion-S-yl)phenol induced a dose- and time-dependent loss of cell viability in rat kidney cortical cells. Cell killing was significantly reduced by inhibition of gamma-glutamyl transpeptidase with Acivicin. p-Aminophenol was also toxic to renal epithelial cells. Coincubation of p-aminophenol with tetraethylammonium bromide, a competitive inhibitor of the organic cation transporter, and with SKF-525A, an inhibitor of cytochrome P450, protected cells from p-aminophenol-induced toxicity. p-Aminophenol would thus be accumulated in the kidney mainly by organic cation transport systems, which are concentrated in the S-1 segment of the proximal tubule. However, p-aminophenol toxicity in vivo is directed toward the S-2 and S-3 segments, which are rich in gamma-glutamyl transpeptidase. These results and the observation that biliary cannulation and glutathione depletion reduce p-aminophenol nephrotoxicity suggest that the biosynthesis of toxic glutathione conjugates is responsible for p-aminophenol nephrotoxicity in vivo. The aminophenol glutathione S-conjugates formed induce p-aminophenol nephrotoxicity by a pathway dependent on gamma-glutamyl transpeptidase.

Aminophenols↗