The Metabolic Rate Constants and Specific Activity of Human and Rat Hepatic Cytochrome P-450 2E1 Toward Toluene and Chloroform

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• Personal Author:
  Alcasey S ; Barton HA ; Evans MV ; Laskey J ; Lipscomb JC ; Snawder, John E. ; Tornero-Velez R
• Description:
  Chloroform (CHCl3) is a near-ubiquitous environmental contaminant, a by-product of the disinfection of drinking water sources and a commercially important compound. Standards for safe exposure have been established based on information defining its toxicity, which is mediated by metabolites. The metabolism of CHCl3 is via cytochrome P-450 2E1 (CYP2E1)-mediated oxidation to phosgene, which is known to obey a saturable mechanism. CYP2E1 is a highly conserved form, expressed in all mammalian systems studied, and is responsible for the metabolism of a great many low-molecular-weight (halogenated) compounds. However, the Michaelis-Menten rate constants for CHCl3 oxidation have not been derived in vitro, and the specific activity of CYP2E1 toward CHCl3 has not been reported. In this investigation with microsomal protein (MSP), apparent V(max) values of 27.6 and 28.3 nmol/h/mg MSP and apparent K(m) values of 1 and 0.15 microM in rats and human organ donors, respectively, were demonstrated. The specific activity of CYP2E1 toward CHCl3 in rats and humans was 5.29 and 5.24 pmol/min/pmol CYP2E1, respectively. Toluene metabolism to benzyl alcohol (BA), another CYP2E1-dependent reaction, was also highly dependent on CYP2E1 content in humans, and was more efficient than was CHCl3 metabolism. The specific activity of human CYP2E1 toward toluene metabolism in human MSP was 23 pmol/min/pmol CYP2E1. These results demonstrate that differences in CYP2E1 content of MSP among individuals and between species are largely responsible for observed differences in toluene and CHCl3 metabolism in vitro. [Description provided by NIOSH]
• Subjects:
  Animals Digestive System Energy Metabolism Environmental Pollution Enzymes Genetics Liver Methyl Chloride Occupational Health Safety Solvents Toluene

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• Keywords:
  Chloromethanes Environmental-contamination Genes Hepatic-microsomal-enzymes Humans In-vitro-study Liver-cells Liver-function Metabolic-rate Metabolism Microsomal-enzymes Oxidation Toluenes

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• ISSN:
  1528-7394
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  North Carolina ; Ohio ; OSHA Region 4 ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DART - Division of Applied Research and Technology
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  67
• Issue:
  7
• NIOSHTIC Number:
  nn:20024735
• Citation:
  J Toxicol Environ Health A 2004 Apr; 67(7):537-553
• Contact Point Address:
  U.S. Environmental Protection Agency, Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH 45268
• Email:
  lipscomb.john@epa.gov
• CAS Registry Number:
  Benzyl alcohol (CAS RN 100-51-6) ; Chloroform (CAS RN 67-66-3) ; Phosgene (CAS RN 75-44-5) ; Toluene (CAS RN 108-88-3)
• Federal Fiscal Year:
  2004
• NORA Priority Area:
  Research Tools and Approaches: Exposure Assessment Methods
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Toxicology and Environmental Health, Part A: Current Issues
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:41dbe0e0df0a0b3efcdd00b5defc3beb22c59cffb2d0c786d55b95fc92ec6da7a8b3eda93c417b798a7b29fd34c48e33aea21de9e8d9f80dc6f3c3e0356f9ce7
• Download URL:
  https://stacks.cdc.gov/view/cdc/196374/cdc_196374_DS1.pdf
• File Type:
  [PDF - 411.72 KB ]