A number of drugs, whose reduced metabolites are capable of undergoing redox cycling, also possess significant teratogenic properties. It has been postulated that the production of reactive oxygen species (ROS) is an important mechanism in chemical teratogenesis. This proposal is designed to utilize fetal liver slices as an in vitro model system to evaluate mechanisms of oxidative damage subsequent to exposure to the anti-epileptic drug, phenytoin, a teratogenic pro-oxidant. The principal investigator will establish dose-response relationships on the expression of a series of biomarkers of oxidative stress and on the induction of apoptosis. These include: oxidant-responsive transcription factors (c-fos, nuclear factor-kappa B), growth arrest and DNA damage genes (Bcl-2, GADD45), tissue glutathione status, lipid membrane damage and the induction of apoptosis. Subsequent to establishment of a relationship between phenytoin exposure and biomarker expression, the impact of prior exposure to a dietary antioxidant (BHA-butylated hydroxyanisole) in preventing the biochemical and cellular consequences of the oxidative stress induced by phenytoin treatment will be examined.
| Gallagher, E P; Sheehy, K M (2001) Effects of phenytoin on glutathione status and oxidative stress biomarker gene mRNA levels in cultured precision human liver slices. Toxicol Sci 59:118-26 |
