Bacterial β-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene and hexachlorobutadiene

Dekant, W.; Vamvakas, Spyridon; Berthold, Klemens; Schmidt, Sabine; Wild, D.; Henschler, D.

doi:10.1016/0009-2797(86)90015-3

Cited by 134 publications

(72 citation statements)

References 25 publications

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“…Therefore, an active GST enzyme will be required to conjugate substrates and form more reactive intermediates that directly damage kidney tissues. Conversely, the deleted variant GST genotype will form an inactive enzyme, and therefore the meta bolism of halo genated compounds will occur through oxidation, without the formation of reactive intermediates in the kidney (11,(32)(33)(34)(35). The same mechanism of GSTT1 dependent bioactivation might be responsible for increased risk of upper urothelial tumors and urinary bladder tumors (36).…”

Section: Discussionmentioning

confidence: 99%

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma

Ćorić¹,

Plješa-Ercegovac²,

Matić³

et al. 2010

Journal of Medical Biochemistry

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izolovana iz krvi 182 kontrolna subjekta i 76 bolesnika sa KBP. Polimorfizam GSTM1 i GSTT1 je odre|ivan metodom PCR-a. Dobijeni rezultati su analizirani u odnosu na faktore rizika za KBP, uklju~uju}i pu{enje i profesionalnu izlo`e nost. U~estalost GSTM1-nultog genotipa je bila vi{a kod bolesnika sa KBP (60,5%) nego kod kontrola (47,2%). Prisustvo GSTT1-nultog genotipa je utvr|eno kod 28,6% kontrola i 27,6% bolesnika sa KBP. Nosioci GSTM1-nultog genotipa imaju 1.9-puta ve}i rizik za KBP (95% CI: 1,06-3,33). Prisustvo GSTT1 aktivnog genotipa je udru `eno sa pove}anim rizikom za KBP kod profesionalno izlo `enih subjekata ka da su kao referentna grupa uzeti neizlo`eni nosici GSTT1-nultog genotipa (OR: 2,48; 95% CI: 1,05-5,86). Nije otkrivena povezanost izme |u nedo statka aktivne forme GSTM1 i GSTT1 i pu{e -nja kod obolelih od KBP. Studija izvedena u Srbiji je pokazala da prisustvo GSTM1 aktivnog genotipa {titi od nastanka KBP, dok prisustvo GSTT1 aktivnog geno tipa pove}ava rizik kod profesionalno izlo`enih osoba.Klju~ne re~i: faktori rizika, glutation S-transferaze, karcinom bubre`nog parenhima, polimorfizamList of non-standard abbreviations: GST -glutathione S-transferase; RCC -renal cell carcinoma; OR -odds ratio, CIconfidence interval Summary: Members of the glutathione S-transferase (GST) superfamily exhibit polymorphic expression. GSTs are investigated as biomarkers of risk for various cancers, including renal cell carcinoma (RCC). The aim of this study was to test the association between GSTM1 and GSTT1 polymorphism and susceptibility to RCC, independently or in conjunction with known risk factors. Genomic DNA was isolated from 182 controls and 76 patients with RCC. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. Data obtained were analyzed with respect to RCC risk factors including smoking and occupational exposure. The frequency of GSTM1-null genotype was higher in patients with RCC (60.5%) compared to controls (47.2%). GSTT1-null genotype was found in 28.6% controls and 27.6% of cases. GSTM1-null individuals exhibit 1.9-fold increased risk of RCC (95% CI: 1.06-3.33). The presence of GSTT1 active genotype was associated with increased risk of RCC in occupationally exposed sub jects when unexposed GSTT1-null subjects were used as a comparison group (OR: 2.48; 95% CI: 1.05-5.86). No association was found between the inactive form of GSTM1 and GSTT1 and smoking in RCC patients. In a Serbian cohort of patients, the presence of a GSTM1 active geno type is protective against RCC, whereas a GSTT1 active geno type increases RCC risk in occupationally exposed subjects.

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Section: Discussionmentioning

confidence: 99%

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma

Ćorić¹,

Plješa-Ercegovac²,

Matić³

et al. 2010

Journal of Medical Biochemistry

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“…, in the University of Wurzburg Institute of Toxicology, Wurzburg, Germany, using procedures published previously (64,65). A GC/MS capture mass spectometer with splitless injection (valve time = 1.0 min) was used to measure N-ac-TCVC and the internal standard, d 3 -N-ac-TCVC.…”

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confidence: 99%

Apartment residents' and day care workers' exposures to tetrachloroethylene and deficits in visual contrast sensitivity.

Schreiber¹,

Hudnell²,

Geller³

et al. 2002

Environ Health Perspect

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Tetrachloroethylene (also called perchloroethylene, or perc), a volatile organic compound, has been the predominant solvent used by the dry-cleaning industry for many years. The U.S. Environmental Protection Agency (EPA) classified perc as a hazardous air pollutant because of its potential adverse impact on human health. Several occupational studies have indicated that chronic, airborne perc exposure adversely affects neurobehavioral functions in workers, particularly visual color discrimination and tasks dependent on rapid visual-information processing. A 1995 study by Altmann and colleagues extended these findings, indicating that environmental perc exposure at a mean level of 4,980 microg/m(3) (median=1,360 microg/m(3)) alters neurobehavioral functions in residents living near dry-cleaning facilities. Although the U.S. EPA has not yet set a reference concentration guideline level for environmental exposure to airborne perc, the New York State Department of Health set an air quality guideline of 100 microg/m(3). In the current residential study, we investigated the potential for perc exposure and neurologic effects, using a battery of visual-system function tests, among healthy members of six families living in two apartment buildings in New York City that contained dry-cleaning facilities on the ground floors. In addition, a day care investigation assessed the potential for perc exposure and effects among workers at a day care center located in the same one-story building as a dry-cleaning facility. Results from the residential study showed a mean exposure level of 778 microg/m(3) perc in indoor air for a mean of 5.8 years, and that perc levels in breath, blood, and urine were 1-2 orders of magnitude in excess of background values. Group-mean visual contrast sensitivity (VCS), a measure of the ability to detect visual patterns, was significantly reduced in the 17 exposed study participants relative to unexposed matched-control participants. The groups did not differ in visual acuity, suggesting that the VCS deficit was of neurologic origin. Healthy workers in the day care investigation were chronically exposed to airborne perc at a mean of 2,150 microg/m(3) for a mean of 4.0 years. Again, group-mean VCS, measured 6 weeks after exposure cessation, was significantly reduced in the nine exposed workers relative to matched controls, and the groups did not differ significantly in visual acuity. These results suggested that chronic, environmental exposure to airborne perc adversely affects neurobehavioral function in healthy individuals. Further research is needed to assess the susceptibility of the young and elderly to perc-induced effects, to determine whether persistent solvent-induced VCS deficits are a risk factor for the development of neurologic disease, and to identify the no observable adverse effect level for chronic, environmental, perc exposure in humans.

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“…The nephrotoxicity and nephrocarcinogenicity of certain halogenated alkenes may be attributable to glutathione S-conjugate formation followed by metabolism of the glutathione S-conjugates to the corresponding cysteine S-conjugates, which are metabolized by renal cysteine conjugate p-lyase (13-lyase) to ammonia, pyruvate, and a thiol (5-7). The thiols thus formed are thought to lose hydrogen halide or tautomerize to yield reactive, electrophilic species (8,9) that may be involved in the production of cell damage and death. The chemical nature of the toxic metabolites formed from cysteine S-conjugates has, however, not been elucidated.…”

mentioning

confidence: 99%

“…Chlorofluoroacetic acid and methyl chlorofluoroacetate were synthesized as described (15). '9F NMR (C2H302H): 8 N,N-Diethyl chlorofluorothioacetamide. Methyl chlorofluoroacetate (30 mmol) was dissolved in 100 ml of diethylamine and was heated at reflux for 6 hr.…”

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confidence: 99%

Bioactivation mechanism of the cytotoxic and nephrotoxic S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine.

Dekant

Lash

Anders

1987

Proc. Natl. Acad. Sci. U.S.A.

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The bioactivation of S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) was studied with purified bovine kidney cysteine conjugate beta-lyase and with N-dodecylpyridoxal bromide in cetyltrimethylammonium bromide micelles as a pyridoxal model system. The beta-lyase and the pyridoxal model system converted CTFC to chlorofluoroacetic acid and inorganic fluoride, which were identified by 19F NMR spectrometry. 2-Chloro-1,1,2-trifluoroethanethiol and chlorofluorothionoacetyl fluoride were formed as metabolites of CTFC and were trapped with benzyl bromide and diethylamine, respectively, to yield benzyl 2-chloro-1,1,2-trifluoroethyl sulfide and N,N-diethyl chlorofluorothioacetamide, which were identified by gas chromatography/mass spectrometry. The bioactivation mechanism of CTFC therefore involves the initial formation of the unstable thiol 2-chloro-1,1,2-trifluoroethanethiol, which loses hydrogen fluoride to form the acylating agent chlorofluorothionoacetyl fluoride; hydrolysis of the thionoacyl fluoride affords the stable, terminal metabolites chlorofluoroacetic acid and inorganic fluoride. The intermediate acylating agent and chlorofluoroacetic acid may contribute to the cytotoxic effects of CTFC.

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Bacterial β-lyase mediated cleavage and mutagenicity of cysteine conjugates derived from the nephrocarcinogenic alkenes trichloroethylene, tetrachloroethylene and hexachlorobutadiene

Cited by 134 publications

References 25 publications

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma

The Role of GSTM1 and GSTT1 Polymorphism in Patients with Renal Cell Carcinoma

Apartment residents' and day care workers' exposures to tetrachloroethylene and deficits in visual contrast sensitivity.

Bioactivation mechanism of the cytotoxic and nephrotoxic S-conjugate S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine.

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