Characterisation of theophylline metabolism by human liver microsomes. Inhibition and immunochemical studies

Richard A. Robson, John O. Miners, Andrew P. Matthews, Ieva Stupans, Debrah Meller, Michael E. McManus, Donald J. Birkett

Research output: Contribution to journalArticlepeer-review

121 Citations (Scopus)


Anti-human NADPH-cytochrome P-450 reductase inhibited all theophylline metabolic path-ways confirming the involvement of cytochrome P-450 isozymes in the metabolism of theophylline. Tolbutamide, debrisoquine, mephenytoin, theobromine, phenylbutazone, sulphaphenazole and sulphinpyrazone did not inhibit theophylline metabolism by human liver microsomes. Verapamil and dextropropoxyphene were non-selective competitive inhibitors of theophylline metabolism. Cimetidine and caffeine selectively inhibited the two demethylations as Ki values for these two pathways were lower than for the 8-hydroxylation pathway. The effects of nifedipine, propranolol and alpha-naphthoflavone were atypical. The degree of inhibition by propranolol reached a plateau, which was greater for the two demethylations than for the 8-hydroxylation. Alpha-naphthoflavone (ANF) at low concentrations inhibited the demethylations to a greater extent than the 8-hydroxylation. At higher concentrations ANF activated all pathways, with this effect being most marked for the 8-hydroxylation. Nifedipine inhibited the theophylline demethylations but not the 8-hydroxylation. In some livers the 8-hydroxylation was markedly activated. The results confirm that there are at least two distinct cytochrome P-450 isozymes involved in theophylline metabolism, one isozyme being involved with the demethylations and a different isozyme involved in the 8-hydroxylation pathway. Preliminary correlation studies suggest that the human orthologue to the rabbit polycyclic hydrocarbon inducible P-450 Form 4 may be involved in the N-demethylations of theophylline.

Original languageEnglish
Pages (from-to)1651-1659
Number of pages9
JournalBiochemical Pharmacology
Issue number9
Publication statusPublished - 1 May 1988
Externally publishedYes


Dive into the research topics of 'Characterisation of theophylline metabolism by human liver microsomes. Inhibition and immunochemical studies'. Together they form a unique fingerprint.

Cite this