PARTICIPATION OF THE CYP2D SUBFAMILY IN LIDOCAINE 3-HYDROXYLATION ANDFORMATION OF A REACTIVE METABOLITE COVALENTLY BOUND TO LIVER MICROSOMAL PROTEIN IN RATS

Lidocaine metabolism was investigated in rat liver microsomes and in a reconstituted system containing P450BTL, a cytochrome (P450) isozyme belonging to the CYP2D subfamily (Suzuki et al., Drug Metab Dispos 20: 367-373, 1992). P450BTL biotransformed lidocaine into 3-hydroxylidoca ine (3-OH-LID) but not monoethylglycinexylidide and 2-methylhydroxylid ocaine, in the reconstituted system including NADPH-P450 reductase and dilauroylphosphatidylcholine. An antibody against P450BTL inhibited m icrosomal lidocaine 3-hydroxylase activity by 97%. Thus, P450BTL and/o r its immunorelated P450 isozyme(s) belonging to the CYP2D subfamily a ppear to be involved in lidocaine 3-hydroxylation. Furthermore, the an tibody also suppressed the amounts of a lidocaine metabolite(s) bound to microsomal protein. These results suggest that the CYP2D subfamily biotransformed lidocaine into 3-OH-LID via an epoxy intermediate, whic h binds to microsomal macromolecules.