Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5561792 | Toxicology | 2017 | 9 Pages |
Exposure to diacetyl and related α-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 α-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 α-diketones is reduction to α-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 α-diketones to the less electrophilic acyloins is a detoxication pathway for α-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 α-diketones with cellular nucleophiles shows that α-diketones react preferentially with arginine residues. Furthermore, the respiratory-tract toxicity and the quantum-chemical reactivity parameters of diacetyl and replacement flavorant α-diketones are similar. Hence, the identified replacement flavorant α-diketones may pose a risk of flavorant-induced respiratory-tract toxicity. The calculated indices for the reaction of α-diketones with arginine support the hypothesis that modification of protein-bound arginine residues is a critical event in α-diketone-induced respiratory-tract toxicity.
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