Flavonoids as inhibitors of rat liver monooxygenase activities.
Flavanone and six hydroxylated derivatives, and cianidanol and eight ethers and esters thereof, were investigated as inhibitors of cytochrome P-450 mediated reactions in rat liver microsomes. The IC50 values towards aminopyrine N-demethylation varied over a 20-fold range and were shown to depend on the pattern of hydroxylation (flavanone derivatives) and on lipophilicity (cianidanol derivatives). In the latter case, a bilinear relationship exists, the optimal log P being 2.92. Using selected compounds, IC50, Km and Vmax values were determined for aminopyrine N-demethylation, biphenyl 4-hydroxylation, and biphenyl 2-hydroxylation. Depending on the inhibitor and on the activity examined, non-competitive, competitive, or mixed inhibition was seen. Interaction with cytochrome P-450 was also studied spectrally and was always found to result in a modified type II difference spectrum (ligand binding). A dual binding mode is postulated, involving electrostatic and lipophilic interactions.
Beyeler
S
S
School of Pharmacy, University of Lausanne, Switzerland.
Testa
B
B
Perrissoud
D
D
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors*; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D005419:Flavonoids / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D005419:Flavonoids; D000633:Aminopyrine N-Demethylase