Differential inhibition of individual human liver cytochromes P-450 by cimetidine.

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Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FP

Differential inhibition of individual human liver cytochromes P-450 by cimetidine.

Gastroenterology. 1991 Dec;101(6):1680-91.

PubMed ID

1955133 [ View in PubMed

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Abstract

Cimetidine binds to cytochrome P-450 and inhibits hepatic metabolism of various drugs in humans. However, cytochrome P-450 is a family of enzymes rather than a single protein, and effects of cimetidine on individual human liver cytochromes P-450 have not been previously characterized. Metabolism of selected substrates and cimetidine-binding assays have been performed using human liver microsomes, purified human liver cytochromes P-450, and cytochrome P-450 complementary DNA-expressed yeast proteins to probe interaction of cimetidine with these individual enzymes. Cimetidine (3.0 mmol/L) in incubations reduced bufuralol hydroxylase activity by 80% and strongly inhibited microsomal nifedipine oxidation (23% +/- 13% of control activity). The same concentration of cimetidine produced intermediate inhibition of cytochrome enzymes responsible for ethoxyresorufin deethylation and aniline hydroxylation (77% +/- 6% and 68% +/- 17% of activity in control microsomal incubations, respectively), but little effect on tolbutamide hydroxylation was observed. Concordantly, the calculated binding constant for the binding of cimetidine to a purified cytochrome P-450 with high tolbutamide hydroxylase activity was 4.4 mmol/L, whereas the calculated binding concentration constant for a purified cytochrome P-450-metabolizing nifedipine was 0.7 mmol/L. These studies show a high variability in the effect of cimetidine on drug metabolism by individual human liver cytochromes P-450. In vitro studies using human liver microsomes and genetically engineered human cytochromes P-450 can be very useful in exploring important clinical questions of hepatic drug metabolism.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Cimetidine	Cytochrome P450 2E1	Protein	Humans	Unknown	Inhibitor	Details