Correlations between embryotoxic and genotoxic effects of phenytoin in mice

Abstract

The anticonvulsant drug phenytoin (DPH) has been suspected to produce embryotoxicity through an arene oxide intermediate. This drug was also found to be a genotoxic agent. These hypotheses were tested in pregnant mice modulating the phases I and II metabolizing enzymes. DPH was studied by assessing embryotoxicity, teratogenicity, and genotoxicity, the latter by the micronucleus test on the polychromatic erythrocytes of dams and fetuses. DPH embryotoxicity was potentiated by inhibiting both cytochrome P-450 and epoxide hydrase and decreased by inducing cytochrome P-450. Equivocal results were obtained by modulating cytochrome P-448. The main DPH metabolite, p-hydroxyphenytoin (HPPH), was ineffective both per se and after cytochrome induction or epoxide hydrase inhibition. DPH did not exert genotoxicity on the maternal organism, no matter which modulating agent was used. In the fetus, however, weak genotoxic effects were observed. These effects significantly increased with inhibition of epoxide hydrase; they disappeared with induction of both cytochromes P-448 and P-450 or with inhibition of the latter. No genotoxicity was exerted by HPPH, even when the enzymatic pattern was modulated. It is concluded that the major role in DPH embryotoxicity is played by the unchanged drug, while the presence of the arene oxide is determinant for genotoxic effects.

Lack of Sister Chromatid Exchange Induction in Phenytoin‐Treated Patients with Epilepsy

“…In recent years, PHT has been suspected of mutagenicity, but the existing evidence is equivocal or contradictory: The slight increase in frameshift mutations observed by Sezzano et al (1982) using the Ames test in Salmonella typhimurium was not confrmed by Leonard et al (1984). Genotoxicity assessment by micronucleus test yielded an increase in polychromatic erythrocytes in fetal Swiss mice following PHT administration to the dams (Barcellona et al, 1987). PHT has been found mutagenic in male germ cells of Swiss mice (Ramaniah et al, 1980).…”