Thioketene formation from .alpha.-haloalkenyl 2-nitrophenyl disulfides: models for biological reactive intermediates of cytotoxic S-conjugates

Dekant, W.; Urban, Gudrun; Goersmann, C.; Anders, M. W.

doi:10.1021/ja00013a090

Cited by 73 publications

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“…The center-of-mass collision energy or relative collision energy is the maximum energy that can be converted from translational energy to internal energy in a two-body collision. models for pyridoxal phosphate-dependent enzymes (9).…”

Section: Introductionmentioning

confidence: 99%

Fourier-Transform Ion Cyclotron Resonance Mass Spectrometric Evidence for the Formation of .alpha.-Chloroenethiolates and Thioketenes from Chloroalkene-Derived, Cytotoxic 4-Thiaalkanoates

Zhang

Wang²,

Hashmi³

et al. 1995

Chem. Res. Toxicol.

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The cytotoxicity of chloroalkene-derived cysteine S-conjugates is thought to be associated with the formation of alpha-chloroenethiolates and thioketenes as reactive intermediates. Recent studies indicate that the formation of 1,2-dichloroethenethiolate, which may give rise to chlorothioketene, is a key step in the bioactivation of 5,6-dichloro-4-thia-5-hexenoic acid (Fitzsimmons et al. (1995) Biochemistry 34, 4276-4286). We report here the use of Fourier-transform ion cyclotron resonance mass spectrometry to provide the first direct evidence for the formation of alpha-chloroenethiolate and thioketene species from a cytotoxic 4-thiaalkanoate. The bioactivation of 5,6-dichloro-4-thia-5-hexenoic acid involves conversion to the corresponding CoA thioester 5,6-dichloro-4-thia-5-hexenoyl-CoA and subsequent processing by the fatty acid beta-oxidation pathway. It has been proposed that the bioactivation of 5,6-dichloro-4-thia-5-hexenoyl-CoA involves loss of 1,2-dichloroethenethiolate, followed by loss of chloride to form chlorothioketene. 1,2-Dichloroethenethiolate and related alpha-chloroalkenethiolates have not been observed directly in aqueous solution. Fourier-transform ion cyclotron resonance mass spectrometric experiments show that S-propyl 5,6-dichloro-4-thia-5-hexenethioate reacts in the gas phase with base (hydroxide ion) to release 1,2-dichloroethenethiolate, which is observed directly in the mass spectrum of the products of the gas-phase reaction. Furthermore, the elimination of chloride from 1,2-dichloroethenethiolate on collision-induced decomposition is facile and provides evidence for chlorothioketene formation. Preliminary evidence for the formation of 1,2-dichloroethenethiolate and chlorothioketene from S-(1,2-dichlorovinyl)-N-acetyl-L-cysteine methyl ester was also obtained. These observations support the intermediacy of alpha-chloroenethiolates and chlorothioketenes in the bioactivation of cytotoxic, chloroalkene-derived 4-thiaalkanoates and cysteine S-conjugates and demonstrate the utility of Fourier-transform ion cyclotron mass spectrometry in studying the formation of reactive intermediates.

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Section: Introductionmentioning

confidence: 99%

Fourier-Transform Ion Cyclotron Resonance Mass Spectrometric Evidence for the Formation of .alpha.-Chloroenethiolates and Thioketenes from Chloroalkene-Derived, Cytotoxic 4-Thiaalkanoates

Zhang

Wang²,

Hashmi³

et al. 1995

Chem. Res. Toxicol.

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“…HCBD is a halogenated alkene that undergoes liver glutathione conjugation and further biotransformation to S-(pentachlrorobutadienyl)-L-cysteine, and it is cleaved by cysteine conjugate β-lyase to a nephrotoxic tioketene in the kidney (Dekant et al, 1991). The hydrocarbon aff ects specifi cally the S 3 segment of the proximal tubule (Ishmael et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of aging influence on renal toxicity caused by segment‐specific nephrotoxicants of the proximal tubule in rat†

Zanetti

Chiusolo

Defazio

et al. 2009

J of Applied Toxicology

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Little is known concerning the sensitivity of aged rats to xenobiotics inducing kidney damage. To increase this knowledge, the age-dependent response of the kidney to hexachloro-1 : 3-butadiene (HCBD) or potassium dichromate (chromate) was investigated. Rats were treated at different ages with a single dose of segment-specific nephrotoxicants of the proximal tubule, chosen on the basis of their specificity for S(3) and for S(1)-S(2) segments, respectively. The toxicological impact of these xenobiotics has been evaluated through biochemical and genomic markers, and histopathological investigation of kidney samples. HCBD treatment induced tubular necrosis of the S(3) segment of the proximal tubule associated with changes of toxicological markers unrelated to the age. In contrast, chromate treatment induced an increased kidney damage related to the rat age. In fact, histopathological investigation revealed that at 1 month of age tubular vacuolar degeneration was seen affecting S(1)-S(2) segments of the proximal tubule, whereas at 3 months of age tubular necrosis occurred in the same segments associated with tubular dilation of the distal portions. Consistently, biochemical analysis confirmed a direct correlation among genomic and biochemical marker variability and animal age. Altogether, the results show that during aging there is an increased sensitivity of kidney to chromate but not to HCBD-induced damage and evidence differential age-related selectivity of rats for nephrotoxic compounds. Significance for human risk assessment is discussed.

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“…Among solvents, hexachlorobutadiene (HCBD) is a halogenated compound that is well known to induce nephrotoxicity in the pars recta of the proximal tubule (Ishmael et al, 1982), owing to metabolic activation to a cysteine S-conjugate with formation of a reactive metabolite in the kidney (Dekant et al, 1991). In addition, accumulation of HD has also been suggested (Birner et al, 1995;Pähler et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Hyaline droplet accumulation in kidney of rats treated with hexachloro‐1:3‐butadiene: influence of age, dose and time‐course

Cristofori

Defazio

Chiusolo

et al. 2011

J of Applied Toxicology

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The present research investigates the occurrence of hyaline droplet (HD) accumulation related to age, dose and time after treatment in male Wistar rats given a single i.p. injection of hexachloro-1:3-butadiene (HCBD). In the study on age, rats from 1 to 12 months of age were treated with 100 mg kg(-1) body weight (b.w.) HCBD dose. Rats treated at 2 months of age showed a greater accumulation of HD than the other age groups; HD accumulation was not observed in 1-month-old rats. In the dose-response study, the treatment with 25, 50 and 100 mg kg(-1) b.w. at 2 months of age caused HD accumulation in the proximal convoluted tubule at all doses, with the 100 mg kg(-1) b.w. group slightly more affected. Finally, in the time-course study, rats treated with a 100 mg kg(-1) b.w. dose at 2 months of age and sacrificed at 6, 12, 24, 48, 72 and 96 h post-dosing showed a time-related HD accumulation in terms of incidence and severity, after 6 h, with a peak at 24 and 48 h and decreasing at 72 and 96 h. The present results show that HD accumulation is an early finding, and is unrelated to dose level and particularly evident in rats of 2 month of age. These findings in male rats treated with HCBD emphasize the importance of considering the age of rats at the start of a study. The more sensitive model was used in the detection of nephrotoxic effects of chemicals.

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Thioketene formation from .alpha.-haloalkenyl 2-nitrophenyl disulfides: models for biological reactive intermediates of cytotoxic S-conjugates

Cited by 73 publications

References 0 publications

Fourier-Transform Ion Cyclotron Resonance Mass Spectrometric Evidence for the Formation of .alpha.-Chloroenethiolates and Thioketenes from Chloroalkene-Derived, Cytotoxic 4-Thiaalkanoates

Fourier-Transform Ion Cyclotron Resonance Mass Spectrometric Evidence for the Formation of .alpha.-Chloroenethiolates and Thioketenes from Chloroalkene-Derived, Cytotoxic 4-Thiaalkanoates

Evaluation of aging influence on renal toxicity caused by segment‐specific nephrotoxicants of the proximal tubule in rat†

Hyaline droplet accumulation in kidney of rats treated with hexachloro‐1:3‐butadiene: influence of age, dose and time‐course

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