Biotransformation of trichloroethene: dose-dependent excretion of 2,2,2-trichloro-metabolites and mercapturic acids in rats and humans after inhalation

Bernauer, Ulrike; Birner, Gerhard; Dekant, W.; Henschler, D.

doi:10.1007/s002040050283

Cited by 86 publications

(70 citation statements)

References 29 publications

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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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“…One of the TCE toxicity mechanisms involves the conjugation with glutathione, which is transformed by ␥-glutamyltransferase and dipeptidase to cysteine S-conjugates Berrnauer et al, 1996;Anders and Dekant, 1998). The formation of cysteine S-conjugates takes place mainly in liver and, to some extent, also in kidney.…”

mentioning

confidence: 99%

Specificity of Aminoacylase III-Mediated Deacetylation of Mercapturic Acids

et al. 2006

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ABSTRACT:Trichloroethylene (TCE) and other halogenated alkenes are known environmental contaminants with cytotoxic and nephrotoxic effects, and are potential carcinogens. Their metabolism via the mercapturate metabolic pathway was shown to lead to their detoxification. The final products of this pathway, mercapturic acids or N-acetyl-L-cysteine S-conjugates, are secreted into the lumen in the renal proximal tubule. The proximal tubule may also deacetylate mercapturic acids, and the resulting cysteine S-conjugates are transformed by cysteine S-conjugate ␤-lyases to nephrotoxic reactive thiols. The specificity and rate of mercapturic acid deacetylation may determine the toxicity of certain mercapturic acids; however, the exact enzymologic processes involved are not known in detail. In the present study we characterized the kinetics of the recently cloned mouse aminoacylase III (AAIII) toward a wide spectrum of halogenated mercapturic acids and N-acetylated amino acids. In general, the V max value of AAIII was significantly larger with chlorinated and brominated mercapturic acids, whereas fluorination significantly decreased it. The enzyme deacetylated mercapturic acids derived from the TCE metabolism including N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NA-1,2-DCVC) and N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine (NA-2,2-DCVC). Both mercapturic acids induced cytotoxicity in mouse proximal tubule mPCT cells expressing AAIII, which was decreased by an inhibitor of ␤-lyase, aminooxyacetate. The toxic effect of NA-2,2-DCVC was smaller than that of NA-1,2-DCVC, indicating that factors other than the intracellular activity of AAIII mediate the cytotoxicity of these mercapturic acids. Our results indicate that in proximal tubule cells, AAIII plays an important role in deacetylating several halogenated mercapturic acids, and this process may be involved in their cyto-and nephrotoxicity.Trichloroethylene (TCE) and other industrial solvents are shown to cause nephrotoxicity and hepatotoxicity, and are probable human carcinogens (Maltoni et al., 1988;Cummings and Lash, 2000). One of the TCE toxicity mechanisms involves the conjugation with glutathione, which is transformed by ␥-glutamyltransferase and dipeptidase to cysteine S-conjugates Berrnauer et al., 1996;Anders and Dekant, 1998). The formation of cysteine S-conjugates takes place mainly in liver and, to some extent, also in kidney. Cysteine S-conjugates may be acetylated in the liver and kidney into corresponding N-acetyl S-conjugates (mercapturic acids) and transported from the liver into the kidney. In the kidney proximal tubules, mercapturic acids may be secreted or deacetylated by aminoacylases into cysteine S-conjugates Dekant, 1994, 1998). The deacetylation reaction may play an important role in the renal nephrotoxicity since cysteine S-conjugates, but not mercapturates, are transformed by cysteine conjugate ␤-lyases into toxic metabolites (Hayden and Stevens, 1990;Commandeur et al., 1995). Cysteine S-conjugates also may be transformed by flavoprotein monooxygenase...

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“…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%

“…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. However, more recent data (143) CHL in the liver, but instead assumes that TCA and TCOH are formed in a fixed yield from the oxidative metabolism of TCE. In the model, TCOH can subsequently be oxidized to TCA, conjugated with glucuronic acid, or reduced to DCA.…”

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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Biotransformation of trichloroethene: dose-dependent excretion of 2,2,2-trichloro-metabolites and mercapturic acids in rats and humans after inhalation

Cited by 86 publications

References 29 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

Specificity of Aminoacylase III-Mediated Deacetylation of Mercapturic Acids

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

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