Abstract

Dose-response studies have been performed using the hepatotoxin 1,1-dichloroethylene (1,1-DCE) to investigate effects of its administration on covalent binding, content of reduced glutathione (GSH), and structural alterations in murine liver. Additionally, these studies have determined if the sites of cellular damage coincided preferentially with the sites of GSH depletion. Treatment with 1,1-DCE evoked dose-dependent alterations in both covalent binding and tissue GSH content. Progressive increases in covalent binding (2.8 +/- 0.8 to 12.5 +/- 1.9 nmol/mg protein) were found within the range of doses tested (75-225 mg/kg). Tissue GSH content (86.4 +/- 6.1 to 35.9 +/- 2.4 nmol/mg protein) declined significantly after 1,1-DCE treatment when compared to that in control mice (128.0 +/- 3.6 nmol/mg protein). Alterations in GSH content due to 1,1-DCE treatment included those associated with significant increases (34-81% of control) in blood volume. Concomitant increases in vascular GSH were observed, and at 225 mg/kg, GSH content comprised 190% of that found in controls. Histochemical staining for GSH exhibited dose-related decreases in staining intensities that were not concentrated in any particular region, but, rather, were uniformly distributed throughout the liver lobule. Liver injury involving centrilobular and midzonal hepatocytes was absent at 75 mg/kg, mild at 125 and 175 mg/kg, and was most severe at 225 mg/kg. The results from these experiments demonstrate dose-dependent relationships between the magnitude of covalent binding of 1,1-DCE metabolite(s), diminished levels of tissue GSH, and hepatocellular necrosis.