THE ROLE OF HEPATOCYTE HETEROGENEITY IN THE INITIATION OF HEPATOCARCINOGENESIS

N-Nitrosodimethylamine (NDMA) is a carcinogen in rat liver while N-nit rosomethylbenzylamine (NMBzA) produces no liver tumors but is a potent esophageal carcinogen in the rat. Both nitrosamines, however, are met abolically activated in the liver and methylate hepatic DNA. The reaso ns for their different carcinogenic properties in rat liver are unclea r. Here we show that as expected, NDMA produces large numbers of putat ive initiated hepatocytes that overexpress the placental form of gluta thione S-transferase (GST-P+ hepatocytes). Hepatocyte division induced by the hepatotoxic effect of NDMA occurs principally in the periporta l region of the liver lobule, while O6-methylguanine formation is prin cipally in the DNA of perivenous cells. These two effects lead to the production of GST-P+ hepatocytes in roughly equal numbers throughout t he liver lobule. NMBzA also induces the formation of a small, but sign ificant number of GST-P+ hepatocytes. The NMBzA-induced GST-P+ hepatoc ytes are localized within the perivenous zone of the liver lobule. Sin ce, unlike NDMA, NMBzA produces no hepatocellular necrosis and hence d oes not induce regenerative cell division, these results suggest that NMBzA initiates only those hepatocytes adjacent to the hepatic vein th at are spontaneously dividing at the time their DNA becomes methylated by the nitrosamine. We used partial hepatectomy to stimulate cell div ision in specific regions of the liver lobule. When the peak of DNA me thylation produced by NMBzA in the perivenous cells coincided with a p eak of cell division in that region, an increased number of GST-P+ hep atocytes was induced. Our results suggest that the potency of initiati ng agents in the liver depends both on their ability to form mutagenic lesions in DNA and to induce division in the specific hepatocytes tha t contain the modified DNA.