title: Oxidative stress and the myelodysplastic syndromes.
abstract: The evolution of higher organisms from anaerobic to aerobic living has promoted an elaborate mechanism of defense against potentially toxic oxidants. Many environmental toxicants implicated in the pathogenesis of myelodysplastic syndromes (MDS), including benzene and ionizing radiation, exert toxicity via pro-oxidant mechanisms. The emerging data suggest a probable genetic susceptibility to environmental carcinogenesis through functional polymorphic variants in enzymes that metabolize toxicants and/or protect against oxidative stress. The most studied enzyme is NAD(P)H:quinone oxidoreductase (NQO1). CD34+ cells from individuals homozygous for the NQO1 C609T nonfunctional allelic variant are incapable of enzyme induction following exposure to benzene, thus potentially increasing the hematotoxicity of benzene metabolites. Serologic and molecular markers of oxidative stress are present in many patients with MDS and include an increased concentration of the lipid peroxidation product malondialdehyde and the presence of oxidized bases in CD34+ cells. Potential mechanisms of oxidative stress include mitochondrial dysfunction via iron overload and mitochondrial DNA mutation, systemic inflammation, and bone marrow stromal defects. The biological activity of the antioxidant aminothiol amifostine in vivo suggests that these pathways may be meaningful targets for future therapy in MDS patients.
authors.affiliation: Molecular and Cellular Pathology, Ninewells Hospital, Dundee, Scotland.
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Farquhar
authors.forename: David T
authors.initials: DT
authors.lastname: Bowen
mesh_terms: D002274:Carcinogens, Environmental / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006801:Humans; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002274:Carcinogens, Environmental; D017382:Reactive Oxygen Species