Oral and intravenous trichloroethylene pharmacokinetics in the rat

D’Souza, Richard; Bruckner, James V.; Feldman, Stuart

doi:10.1080/15287398509530688

Cited by 21 publications

(12 citation statements)

References 33 publications

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“…DISCUSSION TCE is a ubiquitous environmental pollutant in industrialized areas . It easily crosses the gastrointestinal wall and rapidly disappears from the blood , being ex haled unchanged or accumulated in tissues via the blood stream and metabolization (17,22,23). TCE is more rapidly metabolized than PECB or HCB, which were used in our previous studies (3)(4)(5)(6)(7).…”

Section: Resultsmentioning

confidence: 99%

Effects of Sodium Alginate and Fish Oil to Reduce Trichloroethylene Accumulation i Rats.

Ikegami

Umegaki²

1999

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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SummaryThis study was conducted to examine the effect of dietary sodium alginate and fish oil on bodily accumulated trichloroethylene (TCE), which has been widely used as a halogenated solvent and is me tabolized at a high rate. Each of three groups of rats was fed on either of diets containing cellulose-soybean oil (control), Na-alginate-soybean oil or cellulose-fish oil for 3 wk, and thereafter given a single oral dose of TCE (100mg (0.76mmol)/rat). TCE levels in the blood were moni tored for 10h after the administration of TCE. The peak concentrations of TCE in the blood tended to be higher in the alginate and fish oil groups as compared with those in the cellulose-soybean oil group, but not to a significant extent. TCE concentrations in the liver, kidney, brain and the three fat tissues (epididymal, perirenal and subcutaneous) were significantly lower in the alginate and fish oil groups than in the cellu lose-soybean oil group. Fat tissue weights were also lower in the alginate group and fish oil group. The hepatic drug metabolizing enzymes could not account for the remarkable decreases of residual TCE contents in the alginate and fish oil groups. These findings indicate that the metabolism and excretion of TCE might be accelerated in animals with reduced fat tissue mass. Key Words trichloroethylene, Na-alginate, fish oil, accumulation, fat tissueIn previous studies, we have observed that the metabolism and excretion of lipophilic and relatively metabolizable pentachlorobenzene (PECB) were markedly increased in rats when they were fed a restricted diet (1, 2), viscous dietary fibers (3, 4) or fish oil (5, 6). We have also reported that the feeding of fish oil (7) or guar gum (8) to rats enhanced the metabolism and excretion of hexachlorobenzene (HCB),

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Section: Resultsmentioning

confidence: 99%

Effects of Sodium Alginate and Fish Oil to Reduce Trichloroethylene Accumulation i Rats.

Ikegami

Umegaki²

1999

Journal of Nutritional Science and Vitaminology, J Nutr Sci Vit

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“…Most of the PBPK models for TRI have focused on the P450 metabolic pathway and have used the liver as the primary site of metabolism (Abbas and Fisher, 1997;Allen and Fisher, 1993;Dallas et al, 1991;D'Souza et al, 1985;Fisher, 2000;Fisher et al, 1991Fisher et al, , 1998Greenberg et al, 1999). While this approach accounts quantitatively for the majority of the metabolism and toxicity of TRI, it omits the GSH-dependent pathway and the kidney as a target organ.…”

Section: Discussionmentioning

confidence: 99%

“…Although the details of the metabolic pathways for TRI have been extensively studied and several physiologically-based pharmacokinetic (PBPK) models have been described for multiple species, including rats, mice, and humans (Abbas and Fisher, 1997;Allen and Fisher, 1993;Clewell et al, 2000;Dallas et al, 1991;D'Souza et al, 1985;Fisher, 2000;Fisher et al, 1991Fisher et al, , 1998Greenberg et al, 1999), questions remain concerning tissue levels of key metabolites after in vivo exposures to TRI and the relationship between P450-and GST-derived metabolites. Lipscomb et al (1998) developed parameters to correlate data on enzymatic rates and metabolite concentrations in vitro with those in vivo, although additional in vivo data are necessary for validation.…”

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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“…Prout et al (7) administered several doses of labeled TCE (10-2,000 mg/kg) to rats and mice and recovered 93-98% of the radiolabel and reported that peak blood levels occurred in 1 hr in mice and 3 hr in rats. D'Souza et al (14), using classical pharmacokinetic analysis, reported that oral and intravenous bioavailability of TCE was 60-90% in nonfasted rats and greater than 90% in fasted rats. Peak blood levels occurred between 6-10 min and blood concentrations were 2-3 times higher in the fasted rats compared with the nonfasted rats.…”

mentioning

confidence: 99%

Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

250

246

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A major focus in the study of metabolism and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metabolism and to identify those metabolites that are causally associated with toxic responses. Another important issue involves delineation of sex-and species-dependent differences in biotransformation pathways. Defining these differences can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metabolism and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An additional factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metabolism by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metabolism of the cysteine conjugate of TCE by the cysteine conjugate ,B Iyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. A synthesis of this information is then presented to assess how experimental data, from either animals or from in vitro studies, can be extrapolated to humans for risk assessment.

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Oral and intravenous trichloroethylene pharmacokinetics in the rat

Cited by 21 publications

References 33 publications

Effects of Sodium Alginate and Fish Oil to Reduce Trichloroethylene Accumulation i Rats.

Effects of Sodium Alginate and Fish Oil to Reduce Trichloroethylene Accumulation i Rats.

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 of trichloroethylene.

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