METABOLITES AND DNA-BINDING OF CARBAMAZEPINE AND OXCARBAZEPINE IN-VITRO BY RAT-LIVER MICROSOMES

DNA-binding of carbamazepine (CBZ) and oxcarbazepine (OCBZ) catalysed by non-induced, phenobarbital-induced or methylcholanthrene-induced ra t liver microsomes in vitro was studied. C-14-CBZ 200 nmol incubated w ith DNA, liver microsomes and cofactors led to the formation of a sign ificant amount of CBZ-epoxide, which has been suspected as the cause o f teratogenesis and other side-effects of CBZ,(1,2) but has not been r eactive in any test systems for genotoxicity, including the Ames test. (3) No enzyme-dependent DNA-binding of CBZ was found. Using the same c onditions, however, OCBZ was bound to DNA. This binding was dependent on the presence of NADPH. 10-hydroxy-10,11-dihydro-carbamazepine, whic h is known to be the major metabolite of OCBZ, and an unknown peak wer e demonstrated by HPLC. These results are the first indication of a hi gher level of covalent DNA binding of OCBZ than of CBZ. The nature of the unknown metabolite and the pathway leading to covalent binding rem ain to be studied.