Of four H2 blockers, cimetidine, tiotidine, oxmetidine and ranitidine, all except ranitidine showed ligand (type II) interactions with oxidized cytochrome P-450. High- and low-affinity binding sites were observed in hepatic microsomes of control, phenobarbital (PB)-treated and 3-methylcholanthrene (3-MC)-treated rats. All H2 blockers except for ranitidine (up to 400 microM) produced a concentration-dependent inhibitory effect of the metabolic intermediate (MI)-cytochrome P-450 complex formation which is displayed during metabolism of tofenacine in PB hepatic microsomes in vitro. At 400 microM, of all H2 blockers only oxmetidine was able to dissociate in vitro the isosafrole metabolite-cytochrome P-450 complex formed in vivo. Endogenous NADPH-dependent microsomal H2O2 production is inhibited in control, PB and 3-MC microsomes by the H2 blockers to various extents. In liver microsomes of phenobarbital-pretreated rats, substrate-dependent inhibition of H2O2 production correlates with inhibition of MI-cytochrome P-450 complex formation of tofenacine. Moreover, the magnitude of ligand (type II) binding of the H2 blockers correlates with inhibition of H2O2 formation. This indicates that prevention of oxygen activation by ligand binding decreases endogenous H2O2 production. Inhibition of both mono-oxygenase as well as oxidase activity of cytochrome P-450 may lead to adverse drug interactions. On the other hand formation of reactive or deleterious intermediates formed as a consequence of cytochrome P-450 activities can be prevented.