The butter flavorant, diacetyl, forms a covalent adduct with 2-deoxyguanosine, uncoils DNA, and leads to cell death

Diacetyl (DA), a natural butter flavorant, is a causative agent for the lung disease obliterative bronchiolitis. Mutagenic properties of 1,2-dicarbonyls have previously been empirically linked to their possible interaction with DNA nucleobases. This study for the first time identifies chemically the adduct of DA with 2-deoxyguanosine. Selective reactivity of DA with 5'-TTTGTTTTT-3' over 5'-TTTTTTTTT-3' indicated its propensity to modify specifically the guanosine residue. Treatment of plasmid DNA, pBR322, with DA induced changes in electrophoretic mobility that are typical of ternary structure disruption. Such DNA nucleobase interaction of DA translated into increased apoptosis in DA-treated SH-SY5Y cells in a dose-dependent manner (IC(50) = 0.114 ± 0.0421 mM). The traditional carbonyl scavengers metformin, 2-thiobarbituric acid, and d-penicillamine protected cells from DA toxicity in proportion to their rates of reaction with DA, with d-penicillamine causing a maximal increase in the IC(50) to 5.23 ± 0.0992 mM when co-incubated with DA.