Interaction of Cimetidine with Cytochrome P450 and Effect on Mixed-Function Oxidase Activities of Liver Microsomes

• Published in: Human & experimental toxicology Vol. 12; no. 2; pp. 147 - 152
• Main Authors: Faux, S.P., Combes, R.D.
• Format: Journal Article
• Language: English
• Published: Thousand Oaks, CA SAGE Publications 01.03.1993; Arnold
• Subjects: Animals; Biological and medical sciences; Cimetidine - pharmacology; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2B1; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - metabolism; Drug toxicity and drugs side effects treatment; Enzyme Induction - drug effects; Female; In Vitro Techniques; Medical sciences; Methylcholanthrene - pharmacology; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Miscellaneous (drug allergy, mutagens, teratogens...); Mixed Function Oxygenases - metabolism; NADPH-Ferrihemoprotein Reductase - metabolism; Oxidoreductases - metabolism; Pharmacology. Drug treatments; Phenobarbital - pharmacology; Rats; Rats, Wistar; Enzyme inducer; Rat; Enzyme; Toxicity; Cytochrome P450; Rodentia; Microsome; Antihistaminic; In vitro; Vertebrata; Mammalia; H2 receptor; Animal; Flavoprotein-linked monooxygenase
• ISSN: 0960-3271; 1477-0903
• DOI: 10.1177/096032719301200209

The histamine H2-receptor antagonist drug, cimetidine (CM), was investigated to determine its effect on the metabolism of 'model' alkoxyphenoxazone substrates ethoxyresorufin (ER) and pentoxyresorufin (PR). The investigation was carried out under different conditions in rat liver microsomes from rodents pretreated with various classical cytochrome P450 inducers. CM exerted a dual effect on uninduced and PB-induced liver microsomal ethoxyresorufin-O-de-ethylase (EROD) activities; it was initially stimulatory but became inhibitory. However, when 3-MC-induced preparations were used, CM only exerted an inhibitory effect on EROD activity over the whole concentration range (0.01 μM-20 mM). Pre-incubating PB-induced and uninduced liver microsomes with NADPH before the addition of ER and CM decreased the stimulatory effect of CM and increased the inhibitory effect in the concentration range (5-20 mM). With 3-MC-induced preparations, the inhibition of EROD was only marginally potentiated. Overall conclusions for the diphasic effects of CM on biological activities were due to CM binding with differing affinities to different P450s. Subsequent decreases and increases in stimulation and inhibition, respectively, on pre-incubation with NADPH were thought to be due to an increased affinity of CM for reduced cytochrome P450.