Biomedical Engineering Reference
In-Depth Information
7.4 OXIDATIVE STRESS
7.4.1 Oxidative Stress Mechanisms
7.4.1.1 Embryonic Drug Exposure and Reactive Oxygen Species
(ROS) Formation Maternal elimination of a teratogen can be an
important regulator of the amount reaching the embryo, so maternal
pathways such as CYP-catalyzed hydroxylation reactions and UDP-
glucuronosyltransferase-catalyzed drug conjugation are important
determinants of embryonic teratogen exposure (Wells et al., 2005).
However, because ROS, and particularly hydroxyl radicals, are highly
reactive and unlikely to escape the cell in which they are formed, let
alone the tissue or organ, maternal pathways of ROS formation are
unlikely to contribute to embryonic ROS levels, which are determined
by proximate, embryonic pathways. The risk of embryopathies will
likely be determined by a balance among (1) the maternal pathways of
teratogen elimination and (2) embryonic pathways of ROS formation
and detoxification, and repair of ROS-mediated oxidative macro-
molecular damage to cellular macromolecules such as DNA, protein,
and lipids. When an imbalance in these pathways occurs, teratogenesis
can result even at therapeutic drug doses or maternal plasma concen-
trations, or at exposures to levels of environmental chemicals generally
considered to be safe.
Drugs and environmental chemicals can enhance ROS formation via
a number of mechanisms that are not necessarily mutually exclusive for
a given xenobiotic. These mechanisms include (1) enzymatic bioacti-
vation to a free radical intermediate, catalyzed by cytochromes P450s
(CYPs), prostaglandin H synthases (PHSs), and lipoxygenases (LPOs),
among others (Wells et al., 2009b, 2010) (Figure 7.18); (2) superoxide
formation during the metabolism of substrates such as EtOH by
CYP2E1 (Koop, 2006); (3) redox cycling of catechol metabolites
(Wang et al., 2010); (4) interference with the mitochondrial electron
transport chain, producing superoxide (Maritim et al., 2003); and (5)
activation and/or induction of enzymes such as the NOXs that form
superoxide and/or hydrogen peroxide (Lambeth, 2004; Brown and
Griendling, 2009; Jiang et al., 2011) (Figure 7.19).
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