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RESEARCH PRODUCT

Influence of odorant metabolism on human olfactory perception

subject

description

The sense of smell permits the perception of volatile substances commonly known as odors. This sense plays an important role in the feeding and wellness of individuals because it involves exchanges with their environment (search for food or partners, predators detection…). The efficiency of the olfactory system mainly relies on its sensitivity depending on the odorant affinity for their olfactory receptors but also on an enzymatic clearance mechanism of odorants which involves the Odorant metabolizing Enzymes (OME) to avoid the saturation of the receptors. Recent studies have shown that the biotransformation of odorants by EMO, in the olfactory epithelium, participates in the olfactory perception. Indeed, OME catalyse the deactivation of the odorants and their subsequent elimination which led to the termination of the olfactory signal. In this context, this work aims to provide a better understanding of the enzymatic mechanisms of the OME in mammal olfactory perception and to study more specifically these mechanisms in human. The first axis of this work, based on physicochemical analysis, has consisted to develop an innovative proton transfer reaction mass spectrometry technique (PTR-MS) to allow the analysis in real time of the odorants biotransformation by OME. This technique was first applied ex vivo using rats and rabbits olfactory epithelium and olfactory mucus but also in vivo directly inside the human nasal cavity. Thus, we have demonstrated that the olfactory biotransformation of odorants catalyzed by different enzymes like glutathione transferases, carboxylesterases and dicarbonyl xylulose reductases (DCXR), is a very fast mechanism (few milliseconds). This very high velocity is perfectly consistent with the physiological dynamics of the olfactory process. Moreover, PTR-MS analyzes revealed that the odorants biotransformation could produce volatile metabolites with odorous properties which could participate in the global olfactory perception by interacting also with olfactory receptors. These various metabolites have been formally identified by a gas chromatography-mass spectrometry technique (GC-MS). The second axis, based on psychophysical method, evaluated the impact of the odorant metabolism in the human olfactory perception. For this purpose, an original approach recently developed in the lab, consisting of the modulation of the olfactory perception through a competition between odorants metabolized by the same EMO was transposed from the rabbit model to the human. The metabolic competition between several diketones toward DCXR was first demonstrated by biochemical analysis using the corresponding human recombinant enzyme. Then, an olfactometric study carried out on a 40 subjects panel demonstrated that this competition mechanism between odorants induces modulations of the biotransformation of these molecules and thus leads to modifications of their relative bioavailability and in fine of their perception. These new and significant results demonstrate that modulations impacting odorants metabolism leads immediately to changes in their olfactory perception. This thesis highlights on the function of EMO in mammals and reveals for the first time in human a significant role of the odorant metabolism in olfactory perception.