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Human & Experimental Toxicology
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Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice

DH Kim

Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea, College of Veterinary Medicine, Kyungpook National University, Taegu, Korea

EJ Kim

Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea

SS Han

Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea

JK Roh

Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea

TC Jeong

Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea

JH Park

College of Veterinary Medicine, Kyungpook National University, Taegu, Korea

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 H 2-receptor but also inhibit P450 enzymes.

Key Words: H2-blockers • cytochrome P450 • inhibition • mono oxygenases • hexobarbital-induced sleeping time

Human & Experimental Toxicology, Vol. 14, No. 8, 623-629 (1995)
DOI: 10.1177/096032719501400801
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