Upper Respiratory Tract Metabolism of Inspired Alcohol Dehydrogenase and Mixed Function Oxidase Substrate Vapors Under Defined Airflow Conditions

Abstract

Numerous xenobiotic-metabolizing enzymes are present in nasal tissues but little is known about the extent to which inspired vapors are metabolized in that site. In the current study, the metabolism of inspired isoamyl alcohol (an alcohol dehydrogenase substrate), and o-xylene, bromobenzene, and ferrocene (mixed function oxidase [MFO] substrates) was examined by quantitating the effects of metabolic inhibitor pretreatment on uptake of these vapors in the surgically isolated upper respiratory tract (URT) of the F344 rat and Syrian hamster under defined airflow conditions. Constant velocity unidirectional inspiratory flow rates of 35, 70, or 200 ml/min, and 50, 100, and 300 ml/min were used in the hamster and rat, respectively. In both species, URT deposition efficiency of isoamyl alcohol vapor was reduced by 3–6% by pretreatment with the alcohol dehydrogenase inhibitor 4-methylpyrazole (p <.01), providing strong evidence that this vapor was metabolized by nasal alcohol dehydrogenase. Pretreatment with the MFO inhibitor metyrapone decreased nasal deposition efficiency of o-xylene, bromobenzene, or ferrocene by approximately 3–6%, on the average, in either species (p <.05), providing strong evidence that these vapors were metabolized by nasal MFO. The inhibitors were without effect on the uptake of acetone, a nonmetabolized vapor, indicating the selectivity of their effects on the substrate vapors. Apparent in vivo metabolism rates were estimated from the inhibitor-dependent reduction in deposition rate and were also quantitated in vitro. In general, the vapors examined in the study were metabolized more rapidly in vitro by homogenates of the hamster than the rat nasal mucosa. In contrast, the apparent in vivo metabolism rates in the hamster URT were less than that observed in the rat URT. The reasons for this discrepancy are unclear. In both species the estimated in vivo metabolism rate was significantly dependent (p <.05) on the inspiratory flow rate, with a greater degree of metabolism being observed at high compared to low inspiratory flows. The physiological basis for the flow rate dependence is unknown but may relate to regional airflow patterns within the nasal cavity.