Phenytoin administration to pregnant mice: a mutagenic action?

Phenytoin orally administered to pregnant NMRI mice results in limb haemorrhages, necrosis, and in most cases in limb amputations in the offspring. By mating these offspring without any treatment, the same type of abnormalities appeared throughout seven successive generation. In the second and third generation, other malformation, such as haemorrhages of the eyelids, and genitourinary defects were observed. These findings raise the question of the mutagenic role of phenytoin. Phenytoin is a drug of considerable medical use, but very little is known about the various possible intermediate steps involved in its action.