Role of reactive aldehydes in cigarette smoke DNA damage and detoxification mechanisms in lungs and heart: development of urinary biomarkers of exposure

Abstract

Humans are continually exposed to endogenously generated reactive aldehydes or, for example, via exposure to cigarette smoke, burning of fossil fuels and by-products of various industrial processes. Despite the potential health risks, the toxicity of several aldehydes is still poorly studied. Our group found significantly higher levels of adducts of acetaldehyde with 2'-deoxyguanosine in the urine of residents of São Paulo City compared with residents of São João da Boa Vista indicating that these adducts can potentially be used as biomarkers of exposure to pollutants. Also, we found increased levels of this adduct in DNA of rat lungs and brain exposed by inhalation to isotopically labeled acetaldehyde. We developed ultrasensitive methods based on isotopic labeling and LC-MS/MS to quantify aldehyde adducts in tissues, as well as their glutathione and carnosine detoxification products. In collaboration with Prof. Julio Ferreira from ICB-USP, we showed that acetaldehyde in high concentrations causes heart damage in an ex-vivo ischemia/reperfusion model. In this case, acetaldehyde levels not only correlate with the damage but also increases the infarct area. Therefore, the purpose of this project is to investigate the role of these adducts in smokers, looking for biomarkers of exposure in human urine. To compare the levels of aldehyde adducts in rat tissues, specially, lungs and heart and the possible protective role of glutathione and carnosine in aldehyde-mediated damage in ischemia/reperfusion model. Therefore, contributing to the clarification of this mechanism is justified considering the experience of our group in studies of damage to biomolecules promoted by reactive aldehydes. The present project is one of the goals of the CEPID-Redoxoma - to understand how each redox-active intermediate reacts with specific biomolecules and the resulting effects, essential for designing biomarkers and antioxidants. (AU)