Diacetyl and related flavorant α-Diketones: Biotransformation, cellular interactions, and respiratory-tract toxicity

Exposure to diacetyl and related alpha-diketones causes respiratory-tract damage in humans and experimental animals. Chemical toxicity is often associated with covalent modification of cellular nucleophiles by electrophilic chemicals. Electrophilic alpha-diketones may covalently modify nucleophilic arginine residues in critical proteins and, thereby, produce the observed respiratory-tract pathology. The major pathway for the biotransformation of alpha-diketones is reduction to alpha-hydroxyketones (acyloins), which is catalyzed by NAD(P)H-dependent enzymes of the short-chain dehydrogenase/reductase (SDR) and the aldo-keto reductase (AKR) superfamilies. Reduction of alpha-diketones to the less electrophilic acyloins is a detoxication pathway for alpha-diketones. The pyruvate dehydrogenase complex may play a significant role in the biotransformation of diacetyl to CO2. The interaction of toxic electrophilic chemicals with cellular nucleophiles can be predicted by the hard and soft, acids and bases (HSAB) principle. Application of the HSAB principle to the interactions of electrophilic alpha-diketones with cellular nucleophiles shows that alpha-diketones react preferentially with arginine residues. Furthermore, the respiratory-tract toxicity and the quantum-chemical reactivity parameters of diacetyl and replacement flavorant alpha-diketones are similar. Hence, the identified replacement flavorant alpha-diketones may pose a risk of flavorant-induced respiratory-tract toxicity. The calculated indices for the reaction of alpha-diketones with arginine support the hypothesis that modification of protein-bound arginine residues is a critical event in alpha-diketone-induced respiratory-tract toxicity. (C) 2017 Elsevier B.V. All rights reserved.