The goal of research proposed herein is extension of our understanding of the role of biotransformation in teratogenesis. In nearly 20 publications during the past 6 years we have demonstrated the importance of extraembryonic biotransformation as a determinant of the teratogenicity of specific compounds. Following this essentially qualitative phase of work, and analogous to other fields of toxicology, we wish now to determine the specific steps used to activate and inactivate teratogens and how exposures alter these steps qualitatively. We also wish to extend these studies by beginning to analyze the importance of phase II metabolic steps. Unlike study in mutagenicity and carcinogenicity, this is a new area in teratology and may hold keys to species specificity in teratogenic responses as well as enabling predictions of teratogenic potential based on molecular considerations. A second major area we wish to examine concerns metabolic capabilities of the embryo itself and their contribution to teratogen handling. Although most considerations of prenatal drug metabolism have centered around cytochrome P450-dependent steps, we also wish to examine others which may be of greater significance to the embryo, including nitroreduction. We wish to determine whether these capacities are inducible or repressible as we and others have shown for extraembryonic processes. This work is dependent on the development of HPLC profiles and determination of active metabolites generated by extraembryonic and embryonic homogenates in vitro. Metabolites would be generated under conditions found to known to be teratogenic and these would be tested in the embryo culture system and in vivo. Initial study would focus on 3 compounds or groups of compounds, (a) adriamycin (ADR), a commonly used antitumor agent which we have shown to require extraembryonic activation, (b) heterocyclic nitro compunds which we have shown to cause an unique malformation following embryonic activation and (c) rifampicin, which we have shown to cause growth retardation in the unmetabolized state (or metabolized by the embryo) but which requires extraembryonic activation for its teratogenicity. In this way, 2 major areas of metabolism, extraembryonic (maternal) and embryonic would be examined, compared and their contributions to teratogenicity examined for the first time.
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