The study is concerned with the effects of cimetidine (C), ranitidine (R) and oxmetidine (O) on rat liver cells, in order to compare the effects of increasing amounts of the drugs on various metabolic pathways and on hepatocyte morphology, and their relationship with the drug structure, namely the presence of an imidazole or furan ring. In vitro, an inhibition of ethylmorphine N-demethylase (E-DM) (60%) and of aniline hydroxylase (A-OH) (20%) was observed when either C or R were added at a concentration higher than 0.5 mM to microsomes from untreated rats. Microsomes from phenobarbital or 3-methylcholanthrene-pretreated animals showed a 30 to 40% inhibition of E-DM (mixed type inhibition). In vivo, administration of a single dose (475 microM/kg) of R was followed by an inhibition of E-DM activity, significantly less pronounced (p less than 0.05) than following an equimolar amount of C, whereas O did not alter the enzymatic activity. The amount of cytochrome P-450 and the activities of NADPH cytochrome c reductase and of A-OH were substantially unaffected. No changes of smooth endoplasmic reticulum or of other liver cell organelles were observed by electron microscopy. These findings demonstrate that both in vivo and in vitro E-DM appears as the more sensitive among the pathways considered. Moreover the data support the view that the mere presence of the imidazole ring does not account for the inhibitory effect of H2 antagonists.