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

Birner, Gerhard; Vamvakas, Spyridon; Dekant, W.; Henschler, D.

doi:10.2307/3431501

Cited by 26 publications

(43 citation statements)

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“…Principal metabolites recovered in urine include TCA, TCOH and its glucuronide (Lash et al, 2000a). NAcDCVC has been recovered in urine of rats and humans (primarily in an occupational setting) exposed to TRI, although concentrations have typically been <1% of those of the P450-derived metabolites (Bernauer et al, 1996;Birner et al, 1993;Commandeur and Vermeulen, 1990;Dekant et al, 1986). Some have concluded from this that the GST pathway is quantitatively insignificant in the overall metabolism of TRI (Goeptar et al, 1995;Green et al, 1997).…”

Section: Glutathione (Dcvg) S-(12-dichlorovinyl)-l-cysteine (Dcvc)mentioning

confidence: 99%

Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

Lash

Putt

Parker

2006

Journal of Toxicology and Environmental Health, Part A

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Male and female Fischer 344 rats were administered trichloroethylene (TRI) (2, 5, or 15 mmol/kg body weight) in corn oil by oral gavage and TRI and its metabolites were measured at times up to 48 hr in liver, kidney, blood, and urine. We tested the hypothesis that sex-dependent differences in distribution and metabolism of TRI could help explain differences in toxicity. Higher levels of TRI were generally observed in tissues of males. A biphasic pattern of TRI concentration was observed in liver, kidney, and blood of both males and females, consistent with enterohepatic recirculation. Higher concentrations of cytochrome P450 (P450)-derived metabolites (chloral hydrate, trichloroacetate, trichloroethanol) were observed in livers of males than in livers of females whereas the opposite pattern was observed in kidneys. Chloral hydrate was the primary P450-derived metabolite in blood and urine of males whereas trichloroacetate was the primary P450-derived metabolite in blood and urine of females. S-(1,2-Dichlorovinyl)glutathione (DCVG) was recovered in liver and kidney of female rats only and in blood of both male and female rats, with generally higher amounts found in females. S-(1,2-Dichlorovinyl)-L-cysteine (DCVC), the penultimate nephrotoxic metabolite, was recovered in male and female liver, female kidney, male blood, and in urine of both males and females. The results demonstrate sex-dependent differences in recovery of key metabolites of TRI that may help explain differences in susceptibility to TRI-induced toxicity with both the liver and kidney as target organs.

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Section: Glutathione (Dcvg) S-(12-dichlorovinyl)-l-cysteine (Dcvc)mentioning

confidence: 99%

Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

Lash

Putt

Parker

2006

Journal of Toxicology and Environmental Health, Part A

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“…Data for PERC on the relative activity of liver cytosolic GST and kidney cytosolic cysteine conjugate ,B-lyase suggest that the human activity of both enzymes is roughly 10-fold lower than that in the rat (136). On the other hand, the specific activity of N-acetyltransferase in kidney cytosol appears to be very similar across species: 0.41 nmol/min/mg cytosol in the human, compared to 0.35-0.61 in the rat and 0.94 in the mouse (142).…”

Section: Metabolism Oftcementioning

confidence: 91%

“…In the occupational study (142), the concentrations of N-acetyl-DCVC in the workers' urine was about one-third of that measured in rats dosed orally with 50 mg/kg TCE. The ratio of N-acetyl-DCVC to TCA in the workers' urine ranged from 0.03 to 0.3, while in rats it ranged from 0.025 to 0.045, and in mice from 0.014 to 0.065.…”

Section: Metabolism Oftcementioning

confidence: 99%

“…The fact that N-acetyl-DCVC has been identified in the urine of humans exposed to TCE both occupationally (142) and in controlled exposures (143) indicates that exposure of the kidney to DCVC does occur in the human. In the occupational study (142), the concentrations of N-acetyl-DCVC in the workers' urine was about one-third of that measured in rats dosed orally with 50 mg/kg TCE.…”

Section: Metabolism Oftcementioning

confidence: 99%

“…No data were available on the activity of I-lyase in the mouse, so the relationships between P-lyase metabolic parameters in mice and rats reported for trichlorovinylcysteine derived from PERC (136) were assumed to apply-for DCVC as well. For N-acetyltransferase, only specific activity data across species are available (142). These data were converted to the corresponding rate constants (KNATC) by assuming the affinity of N-acetyltransferase for DCVC is the same as that measured for ,B-lyase in the same species.…”

Section: Metabolism Oftcementioning

confidence: 99%

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Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Covington¹,

Clewell²,

Fisher³

2004

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A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concentration curve (AUC) for TCA and DCA in the plasma, the peak concentration and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Additional dose metrics provided for noncancer risk assessment include the peak concentrations and AUCs for TCE and TCOH in the blood, as well as the total metabolism of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, and TCOH concentrations in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating crossspecies differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution.

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Trichlorethen [MAK Value Documentation in German language, 1996]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 22. Lieferung, Ausgabe 1996 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Toxikokinetik und Metabolismus Vergleichende Toxikokinetik bei Maus, Ratte und Mensch Oxidativer Metabolismus Reduktiver Metabolismus Erfahrungen beim Menschen Akute Toxizität Chronische Toxizität Genotoxizität Kanzerogenität Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Leber, Niere Zentralnervensystem Immunsystem Blutbild Wirkung auf Haut und Schleimhäute Reproduktionstoxizität Genotoxizität In vitro In‐vitro‐Genotoxizität der Metaboliten In vivo Bindung an Protein und DNA Kanzerogenität Bewertung

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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

Cited by 26 publications

References 0 publications

Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

Trichlorethen [MAK Value Documentation in German language, 1996]

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