Inhibitory effects of H2-receptor antagonists on cytochrome P450 in male ICR mice.
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-demethylase(ERDM) activities, respectively. It was found that histamine, 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 inhibitory 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.
Kim
D H
DH
Toxicology Research Center, Korea Research Institute of Chemical Technology, Taejon, Korea.
Kim
E J
EJ
Han
S S
SS
Roh
J K
JK
Jeong
T C
TC
Park
J H
JH
D000578:Amidines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D019392:Cytochrome P-450 CYP2E1; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D006591:Hexobarbital / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms
D000578:Amidines; D065607:Cytochrome P-450 Enzyme Inhibitors; D006635:Histamine H2 Antagonists; C096848:IY 80843; C096847:IY 80845; D007093:Imidazoles; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating