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 rat liver microsomes in vitro was studied. 14C-CBZ 200 nmol incubated with DNA, liver microsomes and cofactors led to the formation of a significant amount of CBZ-epoxide, which has been suspected as the cause of teratogenesis and other side-effects of CBZ, 1,2 but has not been reactive in any test systems for genotoxicity, including the Ames test.3 No enzyme-dependent DNA-binding of CBZ was found. Using the same conditions, however, OCBZ was bound to DNA. This binding was dependent on the presence of NADPH. 10-hydroxy-10, 11-dihydro-carbamazepine, which is known to be the major metabolite of OCBZ, and an unknown peak were demonstrated by HPLC. These results are the first indication of a higher level of covalent DNA binding of OCBZ than of CBZ. The nature of the unknown metabolite and the pathway leading to covalent binding remain to be studied.
Castrén
K
K
Department of Pharmacology and Toxicology, University of Oulu.
Pienimäki
P
P
Arvela
P
P
Vähäkangas
K
K
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001665:Binding Sites; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004247:DNA / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D000078330:Oxcarbazepine; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D002220:Carbamazepine; D004247:DNA; D000078330:Oxcarbazepine