COVALENT BINDING OF CARBAMAZEPINE REACTIVE METABOLITES TO P450 ISOFORMS PRESENT IN THE SKIN

Carbamazepine is an anticonvulsant associated with a high risk for sev ere cutaneous reactions. Upon metabolism by cytochrome P450, carbamaze pine may produce reactive metabolites. We evaluated in vitro the coval ent binding of carbamazepine reactive metabolites on human P450s and t hen the presence of these P450s in human epidermis. Carbamazepine reac tive metabolites covalent binding to human liver microsomes involved P 450 subfamilies 1A, 2C and 3A. Specific covalent binding to yeasts exp ressing different P450s showed that carbamazepine reactive metabolites bound specifically to P450 1A2 and 3A4. We confirmed the constitutive presence of P450 3A in human epidermis and after induction with coalt ar of P450 IA. Consequently, the production in epidermis of carbamazep ine reactive metabolites is theoretically possible with formation of P 450 adduct metabolites. (C) 1998 Elsevier Science Ireland Ltd. All rig hts reserved.