Cimetidine: an inhibitor and an inducer of rat liver microsomal cytochrome P-450.
1. Cimetidine pretreatment of male Sprague-Dawley rats caused a significant increase in the specific content of total hepatic cytochrome P-450, supporting the hypothesis that this H2-receptor antagonist has monooxygenase induction effects. 2. Quantitative ultrastructural studies of liver of cimetidine-pretreated animals also supported this hypothesis in showing a significant proliferation of smooth endoplasmic reticulum. These ultrastructural changes were qualitatively similar to those produced by treatment of rats with phenobarbital, a well-characterized monooxygenase-inducing agent whose effects were studied for comparative purposes. 3. Competitive inhibition of metoprolol alpha-hydroxylation by cimetidine in liver microsomes prepared from untreated animals (Ki = 18.8 microM) was also demonstrated. 4. These results allowed testing of the hypothesis (Burnet et al. 1986) that inhibition of a defined monooxygenase should lead to induction of the synthesis of the relevant cytochrome P-450 isozyme. 5. The finding that metoprolol alpha-hydroxylase activity of liver microsomes was lowered, not elevated, by pretreatment of animals with cimetidine argues against the concept of a causal link between monooxygenase inhibition and induction.
Wright
A W
AW
Department of Biochemistry, University of Queensland, Australia.
Winzor
D J
DJ
Reilly
P E
PE
D000818:Animals; D001667:Binding, Competitive; D002927:Cimetidine / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000648:ultrastructure; D004790:Enzyme Induction / Q000187:drug effects; D006900:Hydroxylation; D007425:Intracellular Membranes / Q000648:ultrastructure; D007700:Kinetics; D008297:Male; D008790:Metoprolol / Q000378:metabolism; D008854:Microscopy, Electron; D008862:Microsomes, Liver / Q000201:enzymology* / Q000648:ultrastructure; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D065607:Cytochrome P-450 Enzyme Inhibitors; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D008790:Metoprolol