N-nitrososdimethylamine is activated in microsomes from hepatocytes to reactive metabolites which damage DNA of non-parenchymal cells in rat liver

The liver carcinogen N-nitrosodimethylamine (NDMA) has to be metabolically activated by specific cytochromes before it can react with cellular macromo lecules (e.g. proteins or DNA). Although hepatocytes are believed to be res ponsible for this activation, the liver tumours originate mainly from non-p arenchymal cells (NPC). To investigate their activation capacity we determi ned NDMA-demethylase activity in isolated microsomes from both liver cell t ypes. The results demonstrate that only hepatocytes have activation capacit y. Additional experiments were performed with hepatocytes and NPC using the single cell microgel electrophoresis assay (NIGE). DNA damage appears in b oth cell types following in vivo exposure. Tested in vitro, however, the ca rcinogens induce DNA damages only in hepatocytes (the cells which activate these compounds). N-nitroso-hydroxymethyl-methylamine could be the responsi ble metabolite as it is stable enough to be transported from hepatocytes to NPC in an intact liver. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.