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

• Published in: Biochemical pharmacology Vol. 37; no. 9; p. 1651
• Main Authors: Robson, R A, Miners, J O, Matthews, A P, Stupans, I, Meller, D, McManus, M E, Birkett, D J
• Format: Journal Article
• Language: English
• Published: England 01.05.1988
• Subjects: Adult; Benzoflavones - pharmacology; Caffeine - pharmacology; Cimetidine - pharmacology; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Dextropropoxyphene - pharmacology; Humans; Immunologic Techniques; In Vitro Techniques; Isoenzymes - metabolism; Kinetics; Microsomes, Liver - metabolism; Middle Aged; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Theophylline - metabolism; Verapamil - pharmacology
• ISSN: 0006-2952
• DOI: 10.1016/0006-2952(88)90423-6

Anti-human NADPH-cytochrome P-450 reductase inhibited all theophylline metabolic pathways 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.