Abstract
A large set of xenobiotic-metabolizing enzymes (XMEs), such as the cytochrome P450 monooxygenases (CYPs), esterases and transferases, are highly expressed in mammalian olfactory mucosa (OM). These enzymes are known to catalyze the biotransformation of exogenous compounds to facilitate elimination. However, the functions of these enzymes in the olfactory epithelium are not clearly understood. In addition to protecting against inhaled toxic compounds, these enzymes could also metabolize odorant molecules, and thus modify their stimulating properties or inactivate them. In the present study, we investigated the in vitro biotransformation of odorant molecules in the rat OM and assessed the impact of this metabolism on peripheral olfactory responses. Rat OM was found to efficiently metabolize quinoline, coumarin and isoamyl acetate. Quinoline and coumarin are metabolized by CYPs whereas isoamyl acetate is hydrolyzed by carboxylesterases. Electro-olfactogram (EOG) recordings revealed that the hydroxylated metabolites derived from these odorants elicited lower olfactory response amplitudes than the parent molecules. We also observed that glucurono-conjugated derivatives induced no olfactory signal. Furthermore, we demonstrated that the local application of a CYP inhibitor on rat olfactory epithelium increased EOG responses elicited by quinoline and coumarin. Similarly, the application of a carboxylesterase inhibitor increased the EOG response elicited by isoamyl acetate. This increase in EOG amplitude provoked by XME inhibitors is likely due to enhanced olfactory sensory neuron activation in response to odorant accumulation. Taken together, these findings strongly suggest that biotransformation of odorant molecules by enzymes localized to the olfactory mucosa may change the odorant’s stimulating properties and may facilitate the clearance of odorants to avoid receptor saturation.
Highlights
In mammals, the process of olfaction begins in the olfactory epithelium with the binding of odorant molecules to membrane receptors expressed by olfactory sensory neurons (OSNs)
Because data on odorant biotransformation by the olfactory mucosa (OM) are scarce, we studied the phase I metabolism of several odorant molecules
OM has a High Odorant-metabolizing Capacity In vitro metabolism studies have shown that the rat OM has the capacity to efficiently biotransform odorants such as quinoline, coumarin and isoamyl acetate
Summary
The process of olfaction begins in the olfactory epithelium with the binding of odorant molecules to membrane receptors expressed by olfactory sensory neurons (OSNs). This interaction triggers intracellular reaction cascades that transduce the chemical signal into electrical activity, which is conveyed to the brain for further processing. XMEs catalyze the biotransformation of a wide range of foreign molecules, called xenobiotics, and of many endogenous compounds. Phase II enzymes such as UDP-glucuronosyl transferases (UGTs) or glutathione-S-transferases conjugate metabolites with a polar moiety (e.g., UDP-glucuronic acid, glutathione, etc.) to increase compound hydrophilicity. The last step (phase III) involves transporters that facilitate the excretion of conjugated metabolites from the cell [8,9]
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