Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice

Abstract

1 The present study was undertaken to examine the effects of H₂-receptor antagonists including newly developed mifentidine derivatives, IY-80843 and IY-80845, on cytochrome P450(P450) in vitro and in vivo.

2 Initially, 3-methylcholanthrene-, phenobarbital-, ethanol- and dexamethasone-induced liver microsomes were prepared from male ICR mice to study in vitro effects of above chemicals on ethoxyresorufin O- deethylase(EROD), pentoxyresorufin O-dealkylase(PROD), p-nitrophenol hydroxylase and erythromycin N-demethy lase(ERDM) activities, respectively. It was found that hist amine, cimetidine and famotidine were not inhibitory to four enzyme activities. Meanwhile, mifentidine slightly inhibited EROD and PROD activities and its derivatives IY-80843 and IY-80845 strongly inhibited PROD, EROD and ERDM activities.

3 Prolongation of hexobarbital-induced sleeping time was determined in male ICR mice to confirm in vitro inhibito ry effects of mifentidine and its derivatives in vivo. It was observed that cimetidine, mifentidine, IY-80843 and IY- 80845 caused dose-dependent increases in the sleeping time, indicating the inhibition of P450 responsible for hexobarbital metabolism.

4 It was concluded that mifentidine and its derivatives are P450 inhibitors and that our newly synthesized IY-80843 is most inhibitory.

5 The present results indicate that mifentidine and its derivatives not only antagonise the H₂-receptor but also inhibit P450 enzymes.

Keywords

H2-blockers cytochrome P450 inhibition mono oxygenases hexobarbital-induced sleeping time

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