In vivo and in vitro evaluation of the mutagenic potential of carbamazepine: Does melatonin have anti-mutagenic activity?

The mutagenic potential of carbamazepine (CBZ) therapy has been evaluated both in vivo and in vitro. Analysis of chromosome aberrations (CA), sister chromatid exchanges (SCEs), mitotic and proliferation indices (PRI) were performed. The in vivo study was carried out on 30 patients with idiopathic epilepsy end undergoing treatment with CBZ for different periods starting from 6 months up to 15 years. Plasma CBZ levels were also determined for each patient. The results showed that the total CA and SCEs were significantly increased in CBZ-treated patients. There was no significant correlation between CA and either duration of treatment or the plasma CBZ levels for each patient. The mitotic and proliferation indices were found to be slightly but non-significantly decreased compared to control values. On the other hand, in vitro analysis showed a significant dose-dependent increase in CA and SCEs in human lymphocyte cultures treated with CBZ (4-12 mu g/ml). The mitotic and proliferation indices were also found to be decreased but only significantly in case of high doses of CBZ (12 mu g/ml). Pretreatment of human lymphocytes with melatonin (0.5 mM) exhibited a significant decrease in the frequencies of CBZ-induced CA and SCEs as compared with non-treated cultures. The depressed mitotic and proliferation indices were also found to be improved in cultures pretreated with melatonin. In conclusion, these observations suggest that CBZ monotherapy may lead to chromosome damaging effects (genotoxic) and the use of melatonin as anti-mutagenic agent for human protection against CBZ-induced chromosome damage should be considered. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.