Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: Relative disposition of chloral hydrate to trichloroacetate and trichloroethanol

Apryl Bronley-DeLancey, David C. McMillan, Jo Ellyn M. McMillan, David J. Jollow, Lawrence C. Mohr, David G. Hoel

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background: Trichloroethylene (TCE) is a suspected human carcinogen and a common ground- water contaminant; Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH metabolized to hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenas. (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. Methods: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metaboilism and ALDH/ADH genotype. Thirteen hurnan hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. Results: There was large interindividual variation in the Vmax values for both TCOH and. TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent Despite the large variation Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. Conclusions: These data support the use cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assesment models. The data are discussed with regard to cellular factors, other than genotype that may contribute to the observed variability in metabolism of CH in human liver.

Original languageEnglish (US)
Pages (from-to)1237-1242
Number of pages6
JournalEnvironmental Health Perspectives
Volume114
Issue number8
DOIs
StatePublished - Aug 1 2006

Fingerprint

Chloral Hydrate
Trichloroethylene
aldehyde
Aldehyde Dehydrogenase
trichloroethylene
Risk assessment
Hepatocytes
risk assessment
genotype
Liver
Genotype
Metabolites
Polymorphism
metabolite
polymorphism
Metabolism
metabolism
carcinogen
Cytochrome P-450 CYP2E1
subpopulation

Keywords

  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
  • Chloral hydrate
  • Genetic variability
  • Human hepatocytes
  • Metabolism
  • Risk assessment
  • Trichloroacetate
  • Trichloroethylene

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

Cite this

Application of cryopreserved human hepatocytes in trichloroethylene risk assessment : Relative disposition of chloral hydrate to trichloroacetate and trichloroethanol. / Bronley-DeLancey, Apryl; McMillan, David C.; McMillan, Jo Ellyn M.; Jollow, David J.; Mohr, Lawrence C.; Hoel, David G.

In: Environmental Health Perspectives, Vol. 114, No. 8, 01.08.2006, p. 1237-1242.

Research output: Contribution to journalArticle

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abstract = "Background: Trichloroethylene (TCE) is a suspected human carcinogen and a common ground- water contaminant; Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH metabolized to hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenas. (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. Methods: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metaboilism and ALDH/ADH genotype. Thirteen hurnan hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. Results: There was large interindividual variation in the Vmax values for both TCOH and. TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent Despite the large variation Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. Conclusions: These data support the use cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assesment models. The data are discussed with regard to cellular factors, other than genotype that may contribute to the observed variability in metabolism of CH in human liver.",
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T1 - Application of cryopreserved human hepatocytes in trichloroethylene risk assessment

T2 - Relative disposition of chloral hydrate to trichloroacetate and trichloroethanol

AU - Bronley-DeLancey, Apryl

AU - McMillan, David C.

AU - McMillan, Jo Ellyn M.

AU - Jollow, David J.

AU - Mohr, Lawrence C.

AU - Hoel, David G.

PY - 2006/8/1

Y1 - 2006/8/1

N2 - Background: Trichloroethylene (TCE) is a suspected human carcinogen and a common ground- water contaminant; Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH metabolized to hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenas. (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. Methods: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metaboilism and ALDH/ADH genotype. Thirteen hurnan hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. Results: There was large interindividual variation in the Vmax values for both TCOH and. TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent Despite the large variation Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. Conclusions: These data support the use cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assesment models. The data are discussed with regard to cellular factors, other than genotype that may contribute to the observed variability in metabolism of CH in human liver.

AB - Background: Trichloroethylene (TCE) is a suspected human carcinogen and a common ground- water contaminant; Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH metabolized to hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenas. (ADH). ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. Methods: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metaboilism and ALDH/ADH genotype. Thirteen hurnan hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. Results: There was large interindividual variation in the Vmax values for both TCOH and. TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent Despite the large variation Vmax values among individuals, disposition of CH into the two competing pathways was relatively constant. Conclusions: These data support the use cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assesment models. The data are discussed with regard to cellular factors, other than genotype that may contribute to the observed variability in metabolism of CH in human liver.

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KW - Chloral hydrate

KW - Genetic variability

KW - Human hepatocytes

KW - Metabolism

KW - Risk assessment

KW - Trichloroacetate

KW - Trichloroethylene

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