Reactive Oxygen Species and Toxicity

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. 

Redox reactions are ubiquitous and occur in numerous biological processes. In mitochondrial respiration, ATP production is coupled to electron transport. Electrons are transferred from complex I, II, III, and IV, through a series of redox reactions that create a proton gradient outside of the mitochondrial membrane allowing for the production of ATP. Redox reactions are also extremely important in metabolism. CYPs and FMOs rely on redox reactions for their catalytic function (see Chapter 10). 

Reactive metabolites may cause toxicity in target organs due to transport, or also because of their chemical character and the conditions in a particular microenvironment that may maximize reactivity, as well as the susceptibility of the site to damage. Specific examples of target organ toxicity are described in detail in Chapters 27-35. 

As discussed in Section 20.4.6, many bioactivation reactions can lead to the generation of reactive oxygen species (ROS) through reactions with molecular oxygen. Like 

---

As the superoxide radical is a precursor of the other reactive oxygen species and interacts with blood plasma components under physiological and pathological conditions as well, systems related to its generation are biologically relevant. It should be noted, however, that with respect to the initiation of lipid peroxidation as one of the main causes of oxidative cell damage, its own reactivity is very weak and that only in protonized form is its toxicity comparable to that of lipid peroxyl radicals [18]. 

Gut I, Nedelcheva V, Soucek P, et al. 1996. Cytochromes P450 in benzene metabolism and involvement of their metabolites and reactive oxygen species in toxicity. Environ Health Perspect 104 1211-1218. 

Nitrilotriacetic acid (NTA) is a constituent of various domestic and hospital detergents and is a common water contaminant. NTA forms water-soluble chelate complexes with various metal ions, including iron, at neutral pH. Its iron complex, Fe-NTA, is a known potent nephrotoxic agent. The renal toxicity is assumed to be caused by the elevation of serum free-iron concentration following the reduction of Fe-NTA at the luminal side of the proximal tubule, which generates reactive oxygen species and leads to enhancement of lipid peroxidation. 

Earlier studies have also shown that ricin induces oxidative stress in mice, resulting in increased urinary excretion of MDA and formaldehyde (FA) (Muldoon et al, 1994). Other toxicants have been shown to induce oxidative stress by macrophage activation with subsequent release of reactive oxygen species and tumor necrosis factor alpha (TNF-a). 

Hossain MA., Piyatida P., da Silva JAT., Fujita M. Molecular mechanism of heavy metal toxicity and tolerance in plants central role of glutathione in detoxification of reactive oxygen species and methylglyoxal and in heavy metal chelation. Journal of Botany 2012 Article ID 872875, 37 pages. 

Gobe G, Crane D (2010) Mitochondria, reactive oxygen species and cadmium toxicity in the kidney. Toxicol Lett 198(1 ) 49-55. doi 10.1016/j.toxlet.2010.04.013... 

Anti-inflammatory activity was studied on two labdane derivatives isolated from S. javalambrensis [122-124], that also contains other known diterpenoids [98,99,125]. These two products, ent-13-epi-12a-acetoxy-manoyloxide (76) and e t-8a-hydroxy-labda-13(16), 14-diene (98) were evaluated for anti-inflammatory action in vitro in the concentration range 10 7 M to 10 4 M and were compared with aspirin, sodium salicylate and indomethacine neither compound affected superoxide generation or scavenging and nor did inhibit non-enzymatic lipid peroxidation. These two natural products interact with the eicosanoid system, perhaps at the phospholipase level, but do not interfere with the other tested leukocyte functions or with reactive oxygen species, and are essentially non-toxic to... 

---