Free radical-mediated mechanisms of anti-convulsant teratogenicity

There is limited evidence in animals and humans that at least some fetal anomalies caused by phenytoin and other anti-convulsant drugs may result from toxic plasma concentrations and reversible, receptor-mediated mechanisms. However, increasing evidence, primarily from rodent in vivo and in vitro models, suggests that the teratogenicity of such anti-convulsant drugs, even at therapeutic concentrations, may be due at least in part to their bioactivation to reactive intermediates that irreversibly damage embryonic macromolecular targets. In the case of phenytoin, there is limited evidence from human studies that particularly implicates P450-catalysed bioactivation of phenytoin to an electrophilic arene oxide intermediate which covalently binds to embryonic macromolecules, thereby initiating teratogenesis, with deficient epoxide hydrolase-catalysed detoxification as an important determinant of susceptibility. Substantial evidence from animal models suggests an alternative reactive intermediate-mediated mechanism, involving embryonic peroxidase-catalysed bioactivation of phenytoin and related teratogens to a free radical intermediate that initiates the production of reactive oxygen species. These species cause oxidative stress, resulting in the irreversible oxidation of embryonic cellular macromolecules, which may initiate teratogenesis. The clinical relevance of the latter mechanism, which will have determinants of susceptibility entirely different from those for a P450-dependent electrophilic arene oxide intermediate, awaits further investigation in humans. More than one of these alternative mechanisms may be involved in a given spectrum of anomalies in a particular fetus.