Species Differences in Biotransformation of and Peroxisome Proliferation Due to Trichloroethylene

  • C. R. Elcombe
  • I. S. Pratt
  • T. Green
Conference paper
Part of the Archives of Toxicology book series (TOXICOLOGY, volume 10)

Abstract

The proliferation of hepatic peroxisomes has been linked to an increased incidence of hepatocellular carcinoma in rodents. Trichloroethylene (TRI) administered to mice by gavage for 10 consecutive days elicited dose- dependent hepatic peroxisome proliferation, as determined by increases in cyanide insensitive-palmitoyl CoA oxidation (a peroxisomal ß-oxidation marker enzyme) and increases in peroxisome volume density. TRI did not elicit peroxisome proliferation in rats. Administration of trichloroacetic acid (TCA), a major metabolite of TRI, resulted in dose-dependent peroxisome proliferation in both mice and rats.

Biotransformation studies indicated that mice metabolized TRI to TCA according to dose-dependent linear kinetics. However, in rats, the conversion of TRI to TCA was saturable. It is postulated that the species difference in the hepatocarcinogenicity of TRI (mouse, positive; rat, negative) is due to species differences in peroxisome proliferation, which in turn is a result of species differences in the rate of formation of TCA from TRI. Isolated and cultured hepatocytes were utilized in an attempt to establish a human hazard assessment for TRI-elicited hepatocellular carcinoma. The kinetics of biotransformation of TRI to TCA in isolated hepatocytes was markedly species dependent. The “intrinsic clearance” values (Vmax/Km) for TCA formation in mouse, rat and human hepatocytes were 3.8 × 10-6, 1.2 × 10-7 and 3.2 × 10-8 l/min/106 cells respectively. Furthermore, TCA induced peroxisome proliferation in cultured rat and mouse hepatocytes, but not in cultured human hepatocytes. On this basis, assuming peroxisome proliferation to be causally related to the hepatocarcinogenicity of TRI, it is proposed that TRI represents no significant human hepatocarcinogenic hazard since, (1) human hepatocytes produced TCA at a rate even lower than that of the rat and (2) TCA was not a peroxisome proliferator in human hepatocytes.

Key words

Biotransformation Peroxisomes Trichloroethylene Trichloroacetic acid 

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • C. R. Elcombe
    • 1
  • I. S. Pratt
    • 1
  • T. Green
    • 1
  1. 1.Central Toxicology LaboratoryImperial Chemical Industries PLCMacclesfield, CheshireUK

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