We are studying the toxicology of smoke and tar from environmental sources; to date we have concentrated the greatest effort on tobacco smoke. Our research asks the question: Can the radicals in gas-phase smoke and in tar or soot be responsible for some of the toxicological effects of smoking? We use the techniques of the free radical chemist and biochemist, including kinetics and product analyses, studies of model reactions, and electron spin resonance (ESR) and spin trap methods. Gas-phase smoke contains these radicals (listed in order of decreasing amounts): NO, NO2, alkoxyl radicals (RO.) and carbon-centered radicals (R.). We propose using solid spin traps to identify and quantitate radicals directly from the gas-phase; we will study tobacco smoke and gasoline and diesel automobile exhaust. We have proposed a steady-state hypothesis for the radicals in gas phase cigarette smoke in which radicals are both continuously formed and destroyed. We suggest that NO, which is relatively unreactive, acts as a radical reservoir; we propose that NO is slowly oxidized to the more reactive NO2, which then adds to isoprene to form the radicals we observe. We wish to ask these specific questions: Are the products from the reaction of NO/air/isoprene those that are predicted by this mechanism? Can these products be found in actual cigarette smoke? We also are studying radical chemistry that may be involved in emphysema: We have shown that NO2 reacts with H2O2 (present in the lung) to inactivate human Alpha-1-proteinase inhibitor (a1PI). We now are studying the reactions of NO2 with nM levels of lipid hydroperoxides to produce species that inactivate alPI. For tar, we have shown that the previously assigned structure of the radical is incorrect; the principal paramagnetic species in tar is a quinone/hydroquinone (Q/QH2) complex. We wish to ask these questions: How is this species produced? What chemicals in smoke are its precursor? Does this species bind to DNA? For whole smoke we propose that the gas-phase and tar radicals have opposing effects, one initiating and one retarding radical reactions. We ask: Does tar protect lipids from smoke-initiated autoxidation? Does tar protect alPI from the effects of gas-phase smoke.
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