Reactive oxygen species xenobiotics

Reactive Oxygen Species as Mediators of Drug- and Xenobiotic-Induced DNA Damage... 

REACTIVE OXYGEN SPECIES AS MEDIATORS OF DRUG- AND XENOBIOTIC-INDUCED DNA DAMAGE... 

An example of free radical formation is molecular oxygen, which can accept electrons from a variety of sources to produce reactive oxygen species (ROS) such as the superoxide radical, the hydroxyl radical, and the nitric oxide radical. The superoxide anion radical is formed when one electron is taken up by one of the 2p orbitals of molecular oxygen. Certain drugs and other xenobiotics have the capacity to undergo so-called redox cycles, whereby they provide electrons to molecular oxygen and form super oxide. 

In addition to DNA adducts that occur as a result of covalent binding of reactive intermediates generated by oxidation or conjugation of parent compounds to DNA, reactive oxygen species produced during xenobiotic metabolism can also react with nucleophilic biomolecules. 

The generation of reactive oxygen species (ROS) via normal metabolic processes or exposure to xenobiotics is a challenge that cells need to counteract (see Chapter 20). Metals play prominent roles in the biochemistry of reactive oxygen species as both causal agents and as essential players in enzyme systems that convert ROS to more benign compounds (Figure 21.7). The inability to effectively reduce ROS can lead to lipid peroxidation and eventually cell death. 

It has been shown that the renal bioactivation of xenobiotics such as the herbicides paraquat and diquat [10, 111, 112], and of p-lactams such as cephaloridine and cefsulodin [10, 40, 41] or the antitumor agent adriamycin [113, 114] can induce the generation of reactive oxygen species (oxidative stress) which can be involved in alterations of the structure and functions of cell membranes, cytoskeletal injury, mutagenicity, carcinogenicity, and cell necrosis [115-117]. 

Chronic inflammatory states associated with infection or xenobiotic chemical exposure from the environment can produce genomic lesions that, in time, can become initiated tumors. It is known that hosts do fight microbial infections by moderate production of various free radicals reactive oxygen species (ROS) [e.g., hydroxyl radical (OH ) and the superoxide radical (OT)] or reactive nitrogen species (RNS) [e.g., nitric oxide (NO ) and the strong oxidant, peroxynitrite (ONOO )]. Within limits inflammatory signaling pathways of the host can control excessive free radical concentrations by means of enzymes such as NADPH oxidase, myeloperoxidase, nitric oxide synthase, and others (Federico et al. 2007 Rakoff-Nahonm 2006). 

Bioactivation to a free radical intermediate has been implicated in the teratological mechanism for a number of xenobiotics, including phenytoin and structurally-related AEDs, benzo[a]pyrene, thalidomide, methamphetamine, valproic acid, and cyclophosphamide (Fantel 1996 Wells et al. 2009 Wells and Winn 1996). Unlike in the case of most CYPs, the embryo-fetus has relatively high activities of PHSs and lipoxygenases (LPOs), which via intrinsic or associated hydroperoxidase activity can oxidize xenobiotics to free radical intermediates (Fig. 10) (Wells et al. 2009). These xenobiotic free radical intermediates can in some cases react with double bonds in cellular macromolecules to form covalent adducts, or more often react directly or indirectly with molecular oxygen to initiate the formation of potentially teratogenic reactive oxygen species (ROS). 

Fig. 10 Bioactivation of xenobiotics via the prostaglandin H synthase (PHS) and lipoxygenase (LPO) pathways-postuiated role in teratogenesis. The hydroperoxidase component of embryonic and fetal PHSs, and hydroperoxidases associated with LPOs, can oxidize xenobiotics to free radical intermediates that initiate the formation of reactive oxygen species causing oxidative stress (modified from Yu and Wells 1995)...

Fig. 11 Biochemical pathways for the formation, detoxification, and cellular effects of xenobiotic free radical intermediates and reactive oxygen species (ROS). Fe iron, G-6-P glucose-6-phos-phate, GSH glutathione, GSSG glutathione disulfide, H2O2 hydrogen peroxide, FIO hydroxyl radical, LPO lipoxygenase, NADP nicotinamide adenine dinucleotide phosphate, O2 superoxide, P450 cytochromes P450, PHS prostaglandin H synthase, SOD superoxide dismutase. (Modified from Wells et al. 1997)...

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