We previously postulated that acetaminophen-induced hepatic necrosis in mice results from the formation of a reactive metabolite that arylates vital cellular macro-molecules. While studying species differences in susceptibility to acetaminophen-induced hepatic necrosis, hamsters were found to be particularly vulnerable. We now report the relationships between hepatic glutathione depletion, arylation of hepatic macromolecules in vivo and in vitro and hepatic necrosis after administration of acetaminophen to hamsters.

Preneoplastic and neoplastic liver nodules and hepatocytes isolated from regenerating rat liver have been shown to be resistant to a broad range of carcinogenic agents. This phenomenon was studied by measuring the expression of the multidrug-resistant (mdr) gene in normal liver cells and in preneoplastic and neoplastic nodules and regenerating liver. Levels of messenger RNA for the mdr gene, which encodes P-glycoprotein, were elevated in both preneoplastic and neoplastic lesions. Expression of the mdr gene also reached high levels in regenerating rat liver 24 to 72 hours after partial hepatectomy. These results show that the expression of the mdr gene can be regulated in liver and is likely to be responsible for part of the multidrug-resistance phenotype of carcinogen-initiated hepatocytes and regenerating liver cells.