Occupational exposure to high levels of butter flavoring vapors (BFV) has been associated with the development of bronchiolitis obliterans. BFV contain a variety of compounds, the most prevalent being diacetyl (2,3 butanedione). Inhalation exposure of rats to diacetyl or BFV results in nasal and/or lower airway necrosis and inflammation. Diacetyl is detoxified by dicarbonyl reductase, an enzyme inhibited by butyric acid. Butyric acid is also a component of BFV raising the possibility of an inhalation dosimetric interaction. The current study was aimed at examining this possibility. Towards this end, upper respiratory tract (URT) uptake of diacetyl alone and in combination with butyric acid vapor was measured in the surgically isolated URT of the male Sprague-Dawley rat at constant velocity inspiratory flow rates of 100, 200 or 400 ml/min and exposure concentrations of 100 or 300 ppm. In vitro metabolism kinetics of diacetyl in nasal mucosal homogenates were also assessed. Diacetyl was metabolized in an NADPH-dependent manner in nasal respiratory and olfactory mucosal homogenates. The total activity in olfactory (1.8 umol/min) exceeded that in respiratory mucosa (0.3 umol/min). Both high and low affinity pathways were observed in both tissues. Diacetyl was scrubbed with moderately high efficiency in the URT, with uptake efficiencies of 30-75% being observed depending upon the inspiratory flow rate. Although butyric acid was without effect on URT uptake of a nonmetabolized vapor, diacetyl uptake efficiencies were significantly lower in animals exposed to both 100 ppm diacetyl and 30 ppm butyric acid (36% vs 31%, p=0.02). The selective inhibition of diacetyl uptake provides evidence that diacetyl uptake was dependent on a butyric acid sensitive metabolic pathway, e.g. dicarbonyl reductase. These results suggest that the detoxication enzyme dicarbonyl reductase may be inhibited by the butyric acid vapor present in BFV leading to altered inhalation dosimetry and, perhaps, to an enhancement of diacetyl airway toxicity due to the inhibition of detoxication.
The Toxicologist. Society of Toxicology 47th Annual Meeting and ToxExpo, March 16-20, 2008, Seattle, Washington