EVIDENCE FOR HEPATOCARCINOGENIC ACTIVITY OF PENTACHLOROBENZENE WITH INTRALOBULAR VARIATION IN FOCI INCIDENCE

Pentachlorobenzene (PeCB) is an important environmental contaminant de rived primarily from the by-product contamination of the popular fungi cides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoti ng activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethyl nitrosamine (200 mg/kg body weight) and 2 weeks later were administere d 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 d ays/week. At the end of week 3, rats were subjected to a partial hepat ectomy, Results showed that PeCB, at both doses, significantly increas ed both the number and area of glutathione S-transferase pi (GST-P) fo ci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In ad dition to increases in preneoplastic foci, liver glutathione concentra tions and glutathione-associated enzymes showed significant changes in animals treated with PeCB, Glutathione reductase (GR) and gamma-gluta mylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentratio ns 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 wh ereas 37 and 39% of the foci were centrilobular in the low dose and co ntrol 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 e nvironment may ultimately play a role in negatively selecting for foci growth.