Redox-modulated xenobiotic action and ROS formation: a mirror or a window?
A number of xenobiotics require redox reactions to form the reactive intermediates involved in the ultimate toxic events (e.g., adduct formation). The same mechanisms lead to the formation of reactive oxygen species (ROS), which can themselves exert direct toxicity including, e.g., DNA oxidative damage or glutathione depletion. The occurence of both mechanistic features in xenobiotic activation and toxicity may raise some difficulties in ascertaining the respective roles of reactive intermediates versus ROS-related mechnisms. An example is provided by the toxicity mechanisms of mitomycin C (MMC) and diepoxybutane (DEB), which are commonly referred to as 'cross-linkers'. Their toxic actions, however, are well-known to be modulated via redox parameters, such as oxygen tension, antioxidants levels, or thioredoxin overexpression. The diagnostic assessment of Fanconi's anaemia (FA) relies on MMC and DEB sensitivity, which is usually referred to as 'cross-linker sensitivity'; thus the redox-dependent toxicities of MMC and DEB may have direct implications for the definition of FA phenotype. Another major aspect in ROS formation relies on the extensive evidence pointing to the requirement for oxidative, as well as nitrosative activities in triggering a number of key events in cell division and differentiation, and in early embryogenesis. In turn, antioxidants that may prevent ROS-associated cellular damage in adult cells may prove to exert adverse or fatal outcomes when administered in early life stages. The overall information available on xenobiotic redox biotransformation and on the physiopathological roles of ROS points to the need of addressing ad hoc studies that should take into account the multiplicity of mechanistic events involved.
Pagano
G
G
Italian National Cancer Institute, G Pascale Foundation, Naples, Italy. gbpagano@tin.it
D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002869:Chromosome Aberrations / Q000139:chemically induced; D004249:DNA Damage / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D005199:Fanconi Anemia / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015262:Xenobiotics / Q000494:pharmacology*
D004852:Epoxy Compounds; D017382:Reactive Oxygen Species; D015262:Xenobiotics; D016685:Mitomycin; C007366:diepoxybutane