role of specific cytochrome p450 enzymes in the noxidation of the antiarrhythmic agent mexiletine 1 mexiletine is extensively metabolized in man by c and noxidation and the aim of the present study was to characterize major cytochrome p450 enzymes involved in the formation of nhydroxymexiletine 2 incubations with genetically engineered microsomes indicated that the formation rate of nhydroxymexiletine was highest in the presence of microsomes expressing high levels of either cyp1a2 or cyp2e1 and the formation of nhydroxymexiletine by human liver microsomes was inhibited about 40 by antibodies directed against cyp1a11a2 or cyp2e1 additional incubations demonstrated that formation of nhydroxymexiletine was decreased 47 and 51 by furafylline 40 microm and 120 microm respectively and decreased 55 and 67 by alphanaphthoflavone 1 microm and 3 microm respectively all p 005 versus control 3 the formation rate of nhydroxymexiletine in human liver microsomes was highly correlated with cyp2b6 rsmexiletine r 07827 renantiomer r 07034 senantiomer r 07495 cyp2e1 senantiomer r 07057 and cyp1a2 rsmexiletine r 05334 senantiomer r 06035 4 in conclusion we have demonstrated that cyp1a2 is a major human cytochrome p450 enzyme involved in the formation of nhydroxymexiletine however other cytochrome p450 enzymes cyp2e1 and cyp2b6 also appear to play a role in the noxidation of this drug