ENHANCEMENT BY IRON OF HEPATIC NEOPLASIA IN RATS CAUSED BY HEXACHLOROBENZENE

Female F344 rats received an i.p. injection of iron-dextran (600 mg Fe /kg) and then after 1 week were fed a diet containing 0.02% hexachloro benzene (HCB) for up to 65 weeks. All rats (8/8) which received HCB af ter iron overload developed multiple hepatic nodules whereas only 3/8 rats administered HCB alone had nodules (average of one per positive l iver). These hyperplastic regions were depleted of iron and were often positive for gamma-glutamyl transpeptidase (GGT) and glutathione S-tr ansferase P (GST-P). Telangiectasis and peliosis were prominent featur es in the lesions. Short-term experiments (5-15 weeks of iron/HCB trea tments) showed that GGT and GST-P were induced early in the neoplastic process but not in discrete focal areas. Iron alone also caused some induction of these enzymes. Some cells with induced GST-P in either sh ort or long term experiments also stained positively for this enzyme i n the nucleus. Studies of cytochrome P450 mediated activities showed t hat at 5 and 15 weeks HCB had induced EROD (an estimate of CYP1A1), PR OD (CYP2B1 activity) and BROD activities (CYP2B1 but also other isoenz ymes). Under the influence of iron overload EROD was significantly dep ressed from HCB alone, but not the others or cytochrome P450 reductase . Cytosolic glutathione S-transferase activities were also induced by HCB, but, unlike microsomal EROD, preloading with iron enhanced the ef fects. In contrast, although cytosolic diaphorase activity was induced by HCB, this response was depressed in combination with iron. Glutath ione peroxidase (with H2O2 as substrate) was depressed by both iron an d HCB. Clearly, iron overload potentiates the neoplastic process induc ed by HCB in rats, with both enhancing and depressing effects on vario us enzyme activities induced by this chemical.