IN-VITRO PROGUANIL ACTIVATION TO CYCLOGUANIL BY HUMAN LIVER-MICROSOMES IS MEDIATED BY CYP3A ISOFORMS AS WELL AS BY S-MEPHENYTOIN HYDROXYLASE

1 The activation of proguanil to cycloguanil by human liver microsomes was studied to define the cytochrome P450 (CYP) isoforms involved in this reaction. 2 Apparent K-m values for proguanil ranged from 35 mu M to 183 mu M with microsomes from four human livers. 3 There was a 6.3 -fold range of activity with microsomes from seventeen human livers. R ates of proguanil activation correlated significantly with CYP3A activ ities (benzo[a]pyrene metabolism, caffeine 8-oxidation and omeprazole sulphone formation) and CYP3A immunoreactive content. There was also a highly significant correlation with rates of hydroxyomeprazole format ion. Correlations with activities selective for CYP1A2, CYP2C9/10 and CYP2E1, and with immunoreactive CYP1A2 content were not significant. 4 Proguanil activation was inhibited by R,S-mephenytoin, troleandomycin and by inhibitory anti-CYP3A antiserum and anti-CYP2C IgG and was act ivated by alpha naphthoflavone, Inhibitors selective for CYP1A2, CYP2E 1, CYP2A6 or CYP2C9/10 had little or no effect on proguanil activation . The extents of inhibition by R,S-mephenytoin, troleandomycin and the two antibodies varied with the immunoreactive CYP3A content of the mi crosomes used. 5 It is concluded that proguanil activation to cyclogua nil by human liver microsomes is mediated both by S-mephenytoin hydrox ylase and isoforms of the CYP3A subfamily. This has implications for t he use of proguanil as an in vivo probe for the S-mephenytoin poor met aboliser phenotype.