Use of Kinetic and Mechanistic Data in Species Extrapolation of Bioactivation: Cytochrome P-450 Dependent Trichloroethylene Metabolism at Occupationally Relevant Concentrations

Details

• Personal Author:
  Garrett CM ; Lipscomb JC ; Snawder, John E.
• Description:
  Trichloroethylene (TRI) is an industrial solvent and environmental contaminant; therefore exposure to TRI occurs in diverse human populations. TRI causes hepatocellular carcinoma in B6C3F1 mice, but not rats; this suggests that TRI may be metabolized differently in the two species. We investigated the metabolism of TRI and the effect of TRI on enzymatic activities indicative of specific cytochrome P450 (GYP) forms in hepatic microsomes from mice, rats and humans. Studies in microsomes estimated Michaelis-Menten kinetic parameters by saturation analysis. K-m values were 35.4, 55.5 and 24.6 mu M and V-max values were 5,425, 4,826 and 1,440 pmol/min/mg in pooled mouse, rat and human microsomes, respectively. TRI (1,000 ppm) inhibited CYP2E1 dependent activity in all three species and BROD activity in mice and rats; TRI (1,000 ppm) increased CYP1A1/1A2 activity, and had no effect on CYP2A activity. Inhibition studies with mouse hepatic microsomes demonstrated that TRI was a competitive inhibitor of CYP2E1, with K-i of 50 ppm. TRI noncompetitively inhibited CYP2B-dependent activities in the rat and mouse. Preincubation of microsomes with TRI and NADPH decreased the absorbence of GO-bound CYP in all three species, but the dose-dependence was most evident in mouse hepatic microsomes. These results have quantified the interspecies difference in GYP-dependent TRI bioactivation and indicate that under both equivalent and occupationally relevant (hepatic) exposure conditions the human is at less risk of forming toxic CYP-derived TRI metabolites. [Description provided by NIOSH]
• Subjects:
  Chemistry Environmental Exposure Environmental Health Environmental Pollution Enzymes Laboratories Occupational Health Safety Solvents
• Keywords:
  Chemical-cleaning Chemical-properties Environmental-contamination Environmental-exposure Environmental-health Environmental-pollution Enzymatic-effects Laboratory-animals Laboratory-testing Solvent-vapors
• ISSN:
  1341-9145
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 5 ; OSHA Region 6 ; Texas
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DBBS - Division of Biomedical and Behavioral Sciences
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  110-117
• Volume:
  40
• Issue:
  2
• NIOSHTIC Number:
  nn:20033946
• Citation:
  J Occup Health 1998 Apr; 40(2):110-117
• Contact Point Address:
  JC Lipscomb, US EPA, NCEA, 26 W Martin Luther King Dr, MS 117, Cincinnati, OH 45268
• CAS Registry Number:
  Trichloroethylene (CAS RN 79-01-6)
• Federal Fiscal Year:
  1998
• Peer Reviewed:
  True
• Source Full Name:
  Journal of Occupational Health
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:38d0c9ae673430696203feadcbc297a7888d3793d6ae0e65567dcf33098d50fd481710a3274a3e7f3c8b764751d0361e04e9152f91c22b6e7ebbc143c3324fd7
• Download URL:
  https://stacks.cdc.gov/view/cdc/189344/cdc_189344_DS1.pdf
• File Type:
  [PDF - 661.06 KB ]