Three forms of trichloroethylene-metabolizing enzymes in rat liver induced by ethanol, phenobarbital, and 3-methylcholanthrene

Nakajima, Takahito; Wang, Rui-Sheng; Murayama, Ninzo; Sato, Akio

doi:10.1016/0041-008x(90)90049-z

Cited by 67 publications

(39 citation statements)

References 15 publications

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“…The primary route of metabolism for TCE, shown on the right side of the diagram in Figure 1, is oxidation via the microsomal mixed-function oxidase (MFO) system, now referred to as cytochrome P450, or CYP (96)(97)(98)(99)(100)(101)(102). A minor pathway for TCE metabolism involving conjugation with glutathione (GSH) by glutathione transferase (GST) has also been observed (103).…”

Section: Metabolism Oftcementioning

confidence: 99%

“…To apply these approaches to (100). Sex, pregnancy, and age-related differences in metabolism can result from normal variations in CYP 2E1 content (101); increased metabolism can result from the inducibility of CYP 1A1/2 (e.g., by aromatics), 2B1 (e.g., by phenobarbital), or 2E1 (e.g., by ethanol) (102,115). Studies of human populations have shown that the activity of the CYP enzymes can vary by more than a factor of 10 between individuals (152,174,175), and that there is a genetic difference (polymorphism) between individuals with high activity and low activity that is associated with a different susceptibility to cancer (176).…”

Section: Dose Metric Sdection Uncertaintymentioning

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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Section: Metabolism Oftcementioning

confidence: 99%

Section: Dose Metric Sdection Uncertaintymentioning

confidence: 99%

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

Covington¹,

Clewell²,

Fisher³

2004

View full text Add to dashboard Cite

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“…Phenobarbital induces P-45011B expression, and ethanol induces cytochrome P-45011E1 (Nakajima et al 1990). These isoenzymes differ in molecular weight, spectral properties, electrophoretic mobility, immunological properties, and substrate and product regiospecificity (Ryan et al 1985).…”

Section: -10mentioning

confidence: 99%

“…This suggests that the identification of these chemicals is temperature sensitive. Various steroid metabolizing enzymes coexist with constitutive P-450 and reductase enzymes involved in regulating brain metabolism and xenobiotic detoxification (Vourc'h et al 1992;Akwa et al 1991;Anandatheerthavarada et al 1993;Nakajima et al 1990). Rat brain microsomes contained 0.07 nmol of P-450/mg of protein, which strongly agrees with previously reported levels of P-450 in normal animals at 0.08 nmol of P-450/mg of protein (Anandatheerthavarada et al 1993).…”

Section: Tce and Steroid Metabolismmentioning

confidence: 99%

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United States Air Force Summer Research Program -- 1993. Volume 7. Armstrong Laboratory

Jones¹,

Jabbour²,

Prasad³

et al. 1993

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Metabolism of trichloroethylene and chloral hydrate by the Japanese medaka (Oryzias latipes) in vitro

Lipscomb

Confer

Miller

et al. 1998

Enviro Toxic and Chemistry

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Abstract-Trichloroethylene (TRI), a common groundwater contaminant, is readily metabolized by mammals to produce chloral hydrate (CH), trichloroacetic acid (TCA), and trichloroethanol (TCOH). Cytochrome P450 (CYP) and other enzymes are responsible for formation of these metabolites, which are implicated in TRI's toxicity and carcinogenicity. To establish the validity of the Japanese medaka (Oryzias latipes) as an alternate test species for TRI, we examined the metabolism of TRI and CH, as well as CYP expression, in medaka liver preparations. Trichloroethylene was incubated with medaka microsomal protein, and metabolites were extracted and analyzed using gas chromatography. Microsome-mediated metabolism of TRI was observed, and a K m value for TRI oxidation of 540 M and a V max value of 213 pmol/min·mg Ϫ1 protein were obtained. Conversion of TRI to CH, TCA, and TCOH was found with medaka hepatic subcellular fractions. In addition, a sex difference in hepatic microsomal TRI metabolism, specific CYP content, and ethoxyresorufin O-deethylase activity was noted. The lower specific activity of preparations from the livers of female medaka is compensated for by increased total protein in the larger liver mass of the female. Immunochemical analysis showed that CYP1A was readily detectable in medaka liver, but CYP2E1 was present at very low levels. These data suggest that TRI metabolism in medaka liver preparations mimics that observed in mammalian systems and supports their use as an alternative test species in the evaluation of the toxicity of TRI.

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Three forms of trichloroethylene-metabolizing enzymes in rat liver induced by ethanol, phenobarbital, and 3-methylcholanthrene

Cited by 67 publications

References 15 publications

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

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

United States Air Force Summer Research Program -- 1993. Volume 7. Armstrong Laboratory

Metabolism of trichloroethylene and chloral hydrate by the Japanese medaka (Oryzias latipes) in vitro

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