Evidence for hepatocarcinogenic activity of pentachlorobenzene with intralobular variation in foci incidence.
Pentachlorobenzene (PeCB) is an important environmental contaminant derived primarily from the by-product contamination of the popular fungicides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoting activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethylnitrosamine (200 mg/kg body weight) and 2 weeks later were administered 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 days/week. At the end of week 3, rats were subjected to a partial hepatectomy. Results showed that PeCB, at both doses, significantly increased both the number and area of glutathione S-transferase pi (GST-P) foci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In addition to increases in preneoplastic foci, liver glutathione concentrations and glutathione-associated enzymes showed significant changes in animals treated with PeCB. Glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentrations corresponded with the increase in GR activity with decreases of 40 and 30% in the low and high dose groups, respectively. No significant changes were detected in reduced glutathione concentrations. Together with changes in GR and gamma-GCS expression, a decrease in GST-P foci around the central veins was significant (P = 0.004) at the high dose. In these animals, 26% of the foci were classified as centrilobular whereas 37 and 39% of the foci were centrilobular in the low dose and control groups, respectively. Because of the co-localized nature of the changes in glutathione-associated enzymes and the decreased incidence of centrilobular foci, our results suggest that the reduced cellular environment may ultimately play a role in negatively selecting for foci growth.
Thomas
R S
RS
Center for Environmental Toxicology and Technology, Department of Environmental Health, Colorado State University, Fort Collins 80523-1680, USA. thomas@oncology.wisc.edu
Gustafson
D L
DL
Pott
W A
WA
Long
M E
ME
Benjamin
S A
SA
Yang
R S
RS
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002455:Cell Division; D002722:Chlorobenzenes / Q000633:toxicity*; D005659:Fungicides, Industrial / Q000633:toxicity*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010084:Oxidation-Reduction; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D002722:Chlorobenzenes; D005659:Fungicides, Industrial; C003060:pentachlorobenzene; D005980:Glutathione Reductase; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione