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Human & Experimental Toxicology
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Metabolites and DNA-binding of carbamazepine and oxcarbazepine in vitro by rat liver microsomes

Katariina Castrén

Department of Pharmacology and Toxicology, University of Oulu

Päivi Pienimäki

Department of Pharmacology and Toxicology, University of Oulu

Pentti Arvela

Department of Pharmacology and Toxicology, University of Oulu

Kirsi Vähäkangas

Department of Pharmacology and Toxicology, University of Oulu

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.

Key Words: carbamazepine • oxcarbazepine • DNA-binding • rat liver microsomes • HPLC

Human & Experimental Toxicology, Vol. 15, No. 7, 577-582 (1996)
DOI: 10.1177/096032719601500705
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