The role of hepatocyte heterogeneity in the initiation of hepatocarcinogenesis.

N-Nitrosodimethylamine (NDMA) is a carcinogen in rat liver while N-nitrosomethylbenzylamine (NMBzA) produces no liver tumors but is a potent esophageal carcinogen in the rat. Both nitrosamines, however, are metabolically activated in the liver and methylate hepatic DNA. The reasons for their different carcinogenic properties in rat liver are unclear. Here we show that as expected, NDMA produces large numbers of putative initiated hepatocytes that overexpress the placental form of glutathione S-transferase (GST-P+ hepatocytes). Hepatocyte division induced by the hepatotoxic effect of NDMA occurs principally in the periportal region of the liver lobule, while O6-methylguanine formation is principally in the DNA of perivenous cells. These two effects lead to the production of GST-P+ hepatocytes in roughly equal numbers throughout the liver lobule. NMBzA also induces the formation of a small, but significant number of GST-P+ hepatocytes. The NMBzA-induced GST-P+ hepatocytes are localized within the perivenous zone of the liver lobule. Since, unlike NDMA, NMBzA produces no hepatocellular necrosis and hence does not induce regenerative cell division, these results suggest that NMBzA initiates only those hepatocytes adjacent to the hepatic vein that are spontaneously dividing at the time their DNA becomes methylated by the nitrosamine. We used partial hepatectomy to stimulate cell division in specific regions of the liver lobule. When the peak of DNA methylation produced by NMBzA in the perivenous cells coincided with a peak of cell division in that region, an increased number of GST-P+ hepatocytes was induced. Our results suggest that the potency of initiating agents in the liver depends both on their ability to form mutagenic lesions in DNA and to induce division in the specific hepatocytes that contain the modified DNA.