FREE RADICAL-MEDIATED MECHANISMS OF ANTICONVULSANT TERATOGENICITY

There is limited evidence in animals and humans that at least some fet al anomalies caused by phenytoin and other anti-convulsant drugs may r esult from toxic plasma concentrations and reversible, receptor-mediat ed mechanisms. However, increasing evidence, primarily from rodent in vivo and in vitro models, suggests that the teratogenicity of such ant i-convulsant drugs, even at therapeutic concentrations, may be due at least in part to their bioactivation to reactive intermediates that ir reversibly damage embryonic macromolecular targets. In the case of phe nytoin, there is limited evidence from human studies that particularly implicates P450-catalysed bioactivation of phenytoin to an electrophi lic arene oxide intermediate which covalently binds to embryonic macro molecules, thereby initiating teratogenesis, with deficient epoxide hy drolase-catalysed detoxification as an important determinant of suscep tibility. Substantial evidence from animal models suggests an alternat ive reactive intermediate-mediated mechanism, involving embryonic pero xidase-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 ma y initiate teratogenesis. The clinical relevance of the latter mechani sm, 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 alter native mechanisms may be involved in a given spectrum of anomalies in a particular fetus.