Electron transfer as a potential cause of diacetyl toxicity in popcorn lung disease

Diacetyl, a butter-flavoring component, has recently attracted scientific and media attention because it has been implicated as an agent that induces popcorn lung disease in exposed plant workers. This disease, officially referred to as bronchiolitis obliterans, entails exposure-induced compromise to the lung's epithelial barrier function. In this review, we present a novel molecular mechanism (electron transfer, ET) designed to explain how diacetyl and its imine derivatives might interact to produce lung damage. We relate the fact that diacetyl and related compounds possess reduction potentials amenable to electron transfer (ET) in vivo. The electrochemical nature of these toxicants can potentially disrupt normal ET processes, generate reactive oxygen species (ROS), and participate in cell signaling events. Condensation of diacetyl with protein may also play a role in the toxicity caused by this compound. ET is a common feature of toxic substances, usually involving their metabolites which can operate per se or through reactions that generate ROS and oxidative stress (OS). Examples of agents capable of ET are quinone and metal compounds, aromatic nitro compounds, and iminium salts. Among compounds that generate ET, the alpha-dicarbonyl ET class, of which diacetyl is a member, is much less studied. This review emphasizes diacetyl as an agent that acts through oxidative processes to cause its effects. However, we also treat related substances that appear to act by a similar mechanism. This mechanism forms a theoretical framework capable of describing the mechanism by which diacetyl may induce its effects and is in accord with various physiological activities displayed by other alpha-dicarbonyl substances. Examples of substances that may act by mechanisms similar to that displayed by diacetyl include cyclohexane-1,2-dione, marinopyrroles, reactive carbonyl species, the bacterial signaling agent DPD, and advanced glycation end products.