Inhibition of mono-oxygenase and oxidase activity of rat-hepatic cytochrome P-450 by H₂-receptor blockers

Abstract

1. 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.

2. All H₂ blockers except for ranitidine (up to 400 μm) 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.

3. At 400 μM, of all H₂ blockers only oxmetidine was able to dissociate in vitro the isosafrolc metabolite cytochrome P-450 complex formed in vivo.

4. Endogenous NADPH-dependent mierosoma! H₂O₂ production is inhibited in control, PB and 3-MC microsomes by the H₂ blockers to various extents.

5. In liver microsomes of phenobarbital-pretreated rats, substrate-dependent inhibition of H₂O₂ production correlates with inhibition of Ml-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.

6. 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.