Primary cultures of adult rat hepatocytes — A model for the toxicity of histamine H 2-receptor antagonists

Abstract

Oxmetidine, a potent histamine H 2-receptor antagonist, is cytotoxic to primary cultures of adult rat hepatocytes. The criteria of cellular injury included leakage of cytoplasmic enzymes into the culture medium, inhibition of protein synthesis and measurement of oxygen consumption by freshly isolated hepatocytes. These parameters were correlated with morphological changes in the cells as judged by inverted phase-contrast microscopy. In contrast, two other histamine H 2-receptor antagonists, cimetidine and ranitidine, caused only minor changes in these parameters of cytotoxicity. The extent of injury observed with oxmetidine was both time and concentration dependent and was similar in hepatocytes maintained in culture for 2, 24 or 48 h. Prior treatment of rats with phenobarbital or β-naphthoflavone did not influence oxmetidine-induced cytotoxicity. Inhibitors of cytochrome P-450-mediated monooxygenase activity had little effect on oxmetidine-induced injury with the exception of metyrapone, which was shown to inhibit the observed cytotoxicity by a mechanism other than inhibition of monooxygenase activity. In contrast, the injury could be potentiated by L-ethionine, an antimetabolite which reduces cellular ATP levels, suggesting that oxmetidine induces cytotoxic effects as a consequence of an interaction with intermediary energy metabolism.