Kinetics of Trichloroacetic Acid and Dichloroacetic Acid in the Isolated Perfused Rat Liver

Toxopeus, Corike; Frazier, John M.

doi:10.1006/taap.1998.8505

Cited by 6 publications

(11 citation statements)

References 24 publications

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“…Liver isolation and perfusion. Liver surgery was performed as described previously (Toxopeus and Frazier, 1998). The liver perfusion cabinet was the same as described by Wyman et al (1995).…”

Section: Experimental Methodsmentioning

confidence: 99%

“…To utilize the BBK model to analyze the experimental data for TCA kinetics in the IPRL, the three important factors that control chemical kinetics (metabolism, protein binding, and membrane transport) were addressed as follows. Metabolism plays a negligible role in TCA kinetics (Larson and Bull, 1992;Toxopeus and Frazier, 1998). Therefore, the V MAX for TCA metabolism was set to zero in the generic BBK model.…”

Section: Model Implementationmentioning

confidence: 99%

“…Fitting transport parameters for the canalicular membrane. Since the concentration of TCA in bile was calculated to be similar to that of the free TCA in the liver intracellular water space (Toxopeus and Frazier, 1998), experimental data were fitted assuming that the transport of TCA through the canalicular membrane was linear. In this case the rate of transport was given by:…”

Section: Model Implementationmentioning

confidence: 99%

“…However, exposure of rats to TCA does cause pathological changes in their livers, e.g., lipid peroxidation (Larson and Bull, 1992), peroxisome proliferation (DeAngelo et al, 1989), and liver hypertrophy and glycogen accumulation (Mather et al, 1990). To better understand the disposition of TCA in the liver, detailed studies using the isolated perfused rat liver (IPRL) system were performed in which rat livers were exposed to TCA concentrations of 25 and 250 M (Toxopeus and Frazier, 1998). These studies showed that during a 2-h period only a small fraction of the total TCA dose was taken up and excreted in bile by the liver.…”

mentioning

confidence: 99%

“…The concentration of TCA in bile was calculated to be similar to that of the free TCA in the liver intracellular water space, suggesting that the transport of TCA through the canalicular membrane may be passive. Binding of TCA to bovine serum albumin (BSA) in the perfusion medium was high, over 90% bound (Toxopeus and Frazier, 1998), and was a dominant factor controlling the kinetics of TCA in the IPRL system.…”

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confidence: 99%

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Simulation of Trichloroacetic Acid Kinetics in the Isolated Perfused Rat Liver Using a Biologically Based Kinetic Model

Toxopeus

Frazier²

2002

Toxicological Sciences

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Trichloroacetic acid (TCA) is a contaminant of drinking water. It induces peroxisome proliferation in livers of rats and mice and is hepatocarcinogenic in the latter species. Previous experimental studies of the kinetics of TCA in the isolated perfused rat liver (IPRL) at two doses have been reported. To gain more insight into the mechanistic processes controlling TCA kinetics in the liver a biologically based kinetic (BBK) model for the IPRL was used to analyze the experimental data. The IPRL was exposed to 25, 250, or 1000 microM TCA for 2 h in a recirculating perfusion system. These doses were not cytotoxic. The BBK model simulated the TCA concentration in perfusion medium and liver, and the biliary excretion of TCA. Separate protein binding studies showed that over 90% of TCA was bound to albumin in the perfusion medium whereas binding in liver homogenate was much lower. Integrating the information on protein binding into the BBK model, the hepatic uptake of TCA and its biliary excretion could be fitted assuming asymmetrical saturable transport at the sinusoidal membrane and linear transport at the bile canalicular membrane. To validate the BBK model, additional washout experiments were conducted in which the perfusion medium was replaced with TCA-free medium after 30 min of exposure of the liver to 1000 microM TCA. This approach illustrates the usefulness of BBK modeling for analyzing experimental kinetic data and gaining insight in kinetic mechanisms controlling the behavior of a chemical in the liver.

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Section: Experimental Methodsmentioning

confidence: 99%

Section: Model Implementationmentioning

confidence: 99%

Section: Model Implementationmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Simulation of Trichloroacetic Acid Kinetics in the Isolated Perfused Rat Liver Using a Biologically Based Kinetic Model

Toxopeus

Frazier²

2002

Toxicological Sciences

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Dichloressigsäure und ihre Salze [MAK Value Documentation in German language, 2010]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 49. Lieferung, Ausgabe 2010 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Wirkungsmechanismus Toxikokinetik und Metabolismus Aufnahme, Verteilung, Ausscheidung Metabolismus Erfahrungen beim Menschen Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung Anhang

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In vitro cytogenetic assessment of trichloroacetic acid in human peripheral blood lymphocytes

Varshney

Chandra

Chauhan

et al. 2013

Environ Sci Pollut Res

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Trichloroacetic acid (TCA), a common water disinfection byproduct and a persistent metabolite of trichloroethylene (TCE), has been examined for its genotoxic potential in human lymphocytes. Chromosomal aberration (CA) and cytokinesis-block micronucleus (CBMN) assay were employed to assess the toxicity of TCA. Lymphocytes obtained from three healthy donors were exposed to 25, 50, and 100 μg/ml concentration of TCA separately. TCA exposure resulted in chromosomal anomalies and the formation of micronuclei in lymphocytes. Chromosome analysis revealed the dose-dependent and significant induction of CA. Chromatid break/chromosome break, fragments, and chromatid exchanges were commonly observed. Exposure of higher concentration (50 and 100 μg/ml) significantly inhibited mitotic index. Data obtained with CBMN assay indicated that the induction of micronucleus (MN) formation was greater than that of CA. At 25 μg/ml, TCA induced significant frequencies of MN as compared to control cells. Significant induction of MN at the lowest concentration indicates TCA may also interact with mitotic spindles. Lower percentage of CA and MN at 100 μg/ml as compared to 50 μg/ml indicates occurrence of severe cytotoxicity on exposure of 100 μg/ml TCA in lymphocytes. Collectively, results of both cytogenetic assays indicate that exposure of TCA can induce significant genotoxic and cytotoxic effects.

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Kinetics of Trichloroacetic Acid and Dichloroacetic Acid in the Isolated Perfused Rat Liver

Cited by 6 publications

References 24 publications

Simulation of Trichloroacetic Acid Kinetics in the Isolated Perfused Rat Liver Using a Biologically Based Kinetic Model

Simulation of Trichloroacetic Acid Kinetics in the Isolated Perfused Rat Liver Using a Biologically Based Kinetic Model

Dichloressigsäure und ihre Salze [MAK Value Documentation in German language, 2010]

In vitro cytogenetic assessment of trichloroacetic acid in human peripheral blood lymphocytes

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