STRUCTURE-RELATED INHIBITION OF HUMAN HEPATIC CAFFEINE N3-DEMETHYLATION BY NATURALLY-OCCURRING FLAVONOIDS

The effects of flavonoids on caffeine N3-demethylation, a marker activ ity of CYP1A2, in human liver microsomes were investigated to elucidat e the inhibition mechanism and the structure-activity relationship. Ca ffeine N3-demethylase activity was inhibited by the presence of variou s flavonoids, whose structures seem to be closely related to the degre e of inhibition. Among twenty-one compounds tested, the most active wa s ckrysin with an IC50 value of 0.2 mu M. Others had IC50 values rangi ng from 1 to more than 500 mu M. Kinetic analysis revealed that the me chanism of inhibition varied among the flavonoids. The inhibitory effe ct was postulated to be governed by factors such as the number of hydr oxyl groups and glycosylation of these free hydroxyl groups. An increa se in the number of free hydroxyl groups reduced the inhibitory effect on P450 activity. Analysis of the quantitative structure-activity rel ationship (QSAR) showed that the volume to surface area ratio was the most effective factor on the inhibition of caffeine N3-demethylation, and the electron densities on the C3 and C4' atoms exercised significa nt influence on the inhibitory effect. The calculated inhibitory effec t of flavonoids on CYP1A2 activity was highly correlated with the anti mutagenicity of flavonoids on 2 amino-3,4-dimethylimidazo[4,5-f]quinol ine (MeIQ)-induced umu response. (C) 1998 Elsevier Science Inc.