Affiliation:
1. School of Biological Sciences, Portsmouth Polytechnic, King Henry I Street, Portsmouth PO1 2DY
2. Inveresk Research International Ltd., Tranent EH33 2NE, Scotland, UK
Abstract
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.
Subject
Health, Toxicology and Mutagenesis,Toxicology,General Medicine
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献