TY - JOUR
T1 - Characterisation of theophylline metabolism by human liver microsomes.
T2 - Inhibition and immunochemical studies
AU - Robson, Richard A.
AU - Miners, John O.
AU - Matthews, Andrew P.
AU - Stupans, Ieva
AU - Meller, Debrah
AU - McManus, Michael E.
AU - Birkett, Donald J.
PY - 1988/5/1
Y1 - 1988/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0023918857&partnerID=8YFLogxK
U2 - 10.1016/0006-2952(88)90423-6
DO - 10.1016/0006-2952(88)90423-6
M3 - Article
C2 - 3288213
AN - SCOPUS:0023918857
SN - 0006-2952
VL - 37
SP - 1651
EP - 1659
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 9
ER -