Cytochrome P450-Dependent Metabolism of Trichloroethylene: Interindividual Differences in Humans

Lipscomb, John C.; Garrett, Carol M.; Snawder, John E.

doi:10.1006/taap.1996.8040

Cited by 68 publications

(44 citation statements)

References 31 publications

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“…CYP1A2 activity was significantly lower in the low-Km group than in the other two groups, and CYP2E1 activity was significantly higher in the high-Km group than in the two other groups, but no differences were observed for CYP3A4 activity among the three groups. Lipscomb et al (64) also found that CYP2E1 was the primary isoform responsible for TCE metabolism, accounting for > 60% of total microsomal metabolism. These results indicate that the capacity of humans to metabolize TCE will vary considerably and that factors that alter P450 activity, in particular CYP2E1 activity, can alter TCE metabolism and hence, susceptibility to TCE-induced toxicity.…”

Section: Variations Among Humansmentioning

confidence: 96%

“…Overall rates of TCE metabolism vary considerably between the various experimental species that are used in laboratory investigations (i.e., rats, mice, rabbits) and between these species and humans (64). In practical terms, more complete documentation and understanding of sex-and species-dependent differences in metabolism will enable refinements in risk assessment (35,64,65), so that default assumptions can be significantly different than the actual situation in humans.…”

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 99%

“…In practical terms, more complete documentation and understanding of sex-and species-dependent differences in metabolism will enable refinements in risk assessment (35,64,65), so that default assumptions can be significantly different than the actual situation in humans. However, the observed variations are often beyond allometric expectations, suggesting that more complex metabolic and other differences exist between species.…”

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 99%

“…Lipscomb et al (64) observed considerable variability in the P450-catalyzed oxidation of TCE in 23 samples of human liver microsomes. Km values for TCE (28.3 ± 12.9 pM; mean ± SD, n = 23) varied over a more than a fourfold concentration range (range = 12.6-55.7 pM) and were not normally distributed.…”

Section: Variations Among Humansmentioning

confidence: 99%

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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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Section: Variations Among Humansmentioning

confidence: 96%

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 99%

Section: Descrption Ofoxidative Pathways Oftce Metabolismmentioning

confidence: 99%

Section: Variations Among Humansmentioning

confidence: 99%

See 2 more Smart Citations

Metabolism of trichloroethylene.

Lash

Fisher

Lipscomb

et al. 2000

Environ Health Perspect

250

246

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“…The increased availability of human liver tissue enabled the construction of a bank of frozen human liver samples that were analyzed for protein content, cytochrome P450 2E1 content (Lipscomb et al, 2003b), and oxidative activity toward trichloroethylene (Lipscomb et al, 1997). The data were log-normally distributed and the 5 th and 95 th percentiles of the distribution of trichloroethylene oxidized per minute per gram liver differed by approximately 6-fold.…”

Section: Examples Of In Vitro To In Vivo Extrapolationmentioning

confidence: 99%

Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

Lipscomb

Meek

Krishnan³

et al. 2004

Toxicology Mechanisms and Methods

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Risk assessment methodologies are being updated to allow the inclusion of numerical values for variance in pharmacokinetic (PK) measures and pharmacodynamic (PD) processes related to toxicity. The key PK measures and PD processes are identified from the results of carefully conducted and adequately reported studies. In some instances, studies with humans are not possible, and so the development of data useful for human PK evaluations and on PD processes in vitro or in silico represent an alternative. These results can be integrated under physiologic, anatomic and biochemical constraints of the intact body through physiologically based pharmacokinetic (PBPK) modeling. This manuscript presents the rational for and key considerations related to the inclusion of quantitative PK and PD data in assessing chemical risks.2

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Trichlorethen, Addendum [BAT Value Documentation in German language, 2003]

Bolt¹

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Biologische Arbeitsstoff‐Toleranz‐Werte (BAT‐Werte) und Expositionsäquivalente für krebserzeugende Arbeitsstoffe (EKA) , 11. Lieferung, Ausgabe 2003 Der Artikel enthält folgende Kapitel: Evaluierung der biologischen Expositionsäquivalente Metabolismus und Kinetik Kritische Toxizität Auswahl der Indikatoren Untersuchungsmethoden Expositionsäquivalente krebserzeugender Arbeitsstoffe (EKA) Interpretation von Untersuchungsdaten

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Cytochrome P450-Dependent Metabolism of Trichloroethylene: Interindividual Differences in Humans

Cited by 68 publications

References 31 publications

Metabolism of trichloroethylene.

Metabolism of trichloroethylene.

Incorporation of Pharmacokinetic and Pharmacodynamic Data into Risk Assessments

Trichlorethen, Addendum [BAT Value Documentation in German language, 2003]

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