5.05 - The Role of Biotransformation in Developmental Toxicity

Abstract

Biotransformation within both the mother and her developing embryo and fetus can play a variety of important roles in determining developmental toxicity or teratogenicity. Although the term “biotransformation” is typically associated with the metabolism of drugs and endogenous substrates, we have expanded this term to include reactions involved particularly in the formation and detoxification of reactive oxygen species, and the repair of oxidatively damaged DNA. The mother’s metabolism of a drug or environmental chemical (xenobiotic) can determine its elimination, thereby regulating the maternal plasma concentration of the xenobiotic, which in turn determines how much is available for transfer to the developing embryo or fetus. Once in the embryo or fetus, conceptal “bioactivating” pathways may convert a relatively nontoxic xenobiotic to a highly reactive and potentially toxic intermediary metabolite, such as an electrophilic or free radical intermediate, which can covalently (irreversibly) bind to or oxidatively damage embryonic cellular macromolecules such as DNA, RNA, proteins, and lipids, and/or directly alter cellular signal transduction. Oxidative damage and altered signal transduction are also caused by reactive oxygen species (ROS), which can be initiated by a drug-free radical or by drug-induced increases in endogenous pathways of ROS formation, such as ROS-producing NADPH oxidases (NOX). A teratogenic outcome will be dependent in part upon the mitigating protective effects of embryonic biotransforming pathways that detoxify either the xenobiotic reactive intermediate or the ROS initiated by some xenobiotics. A subsequent level of protection is afforded by embryonic pathways for the repair or removal of damaged cellular macromolecules. The regulatory effects of maternal xenobiotic metabolism and the balance among embryonic pathways of bioactivation and ROS formation, reactive intermediate and ROS detoxification, and repair of cellular macromolecules together determine the adverse developmental outcomes of xenobiotic exposure during pregnancy. Individual maternal and embryonic differences in these pathways of biotransformation, due to either genetic or environmental factors, can therefore constitute important determinants of risk.