gain a deeper understanding of XME activity on flavor perception.

## ACKNOWLEDGMENTS

This work was supported by the "Agence Nationale de la Recherche" (ANR), Grant Numbers: ANR-16-CE21-0004, ANR-14-CE20-0001, and ANR-20-CE21-0002. Mathieu Schwartz was supported by the INRAE TRANSFORM department (ANS CrysFlavor). Carolina Muñoz-González thanks the Atracción de Talento programme (2019T1/BIO13748).

## AUTHOR CONTRIBUTIONS

Mathieu Schwartz drafted the manuscript with input from all authors. Fabrice Neiers, Jean-Philippe Charles, Jean-Philippe Charles, Carolina Muñoz-González, Gilles Feron, Francis Canon, and Mathieu Schwartz revised the manuscript. All authors have approved the submitted version.

## CONFLICT OF INTEREST

The authors declare no conflict of interest.

## ORCID

Francis Canon https://orcid.org/0000-0002-6140-5007

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Dinu, V., Kilic, A., Wang, Q., Ayed, C., Fadel, A., Harding, S. E., Yakubov, GE, & Fisk, I. D. (2020). Policy, toxicology and physico-chemical considerations on the inhalation of high concentrations of food flavour. *npj Science of Food*, **4**, 15. https://doi.org/10.1038/s41538-020-00075-y

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Dufosse, L., Latrasse, A., & Spinnler, H.-E. (1994). Importance of lactones in food flavours: Structure, distribution, sensory properties and biosynthesis. *Sciences des Aliments*. **14**, 17–50. https://hal.archives-ouvertes.fr/hal-02637614

Edenberg, H. J., & McClintick, J. N. (2018). Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: A critical review. *Alcoholism, Clinical and Experimental Research*, **42**(12), 2281–2297. https://doi.org/10.1111/acer.13904

Endo, S., Matsunaga, T., Kitade, Y., Ohno, S., Tajima, K., El-Kabbani, O., & Hara, A. (2008). Human carbonyl reductase 4 is a mitochondrial NADPH-dependent quinone reductase. *Biochemical and Biophysical Research Communications*, **377**(4), 1326–1330. https://doi.org/10.1016/j.bbrc.2008.11.003

Endo, S., Miyagi, N., Matsunaga, T., Hara, A., & Ikari, A. (2016). Human dehydrogenase/reductase (SDR family) member 11 is a novel type of 17beta-hydroxysteroid dehydrogenase. *Biochemical and Biophysical Research Communications*, **472**(1), 231–236. https://doi.org/10.1016/j.bbrc.2016.01.190

Engeland, K., Hoog, J. O., Holmquist, B., Estonius, M., Jornvall, H., & Vallee, B. L. (1993). Mutation of Arg-115 of human class III alcohol dehydrogenase: A binding site required for formaldehyde dehydrogenase activity and fatty acid activation. *PNAS*, **90**(6), 2491–2494. https://doi.org/10.1073/pnas.90.6.2491

Fabrini, R., Bocedi, A., Camerini, S., Fusetti, M., Ottaviani, F., Pas-sali, F. M., Topazio, D., Iavarone, F., Francia, I, Castagnola, M., & Ricci, G. (2014). Inactivation of human salivary glutathione trans-ferase P1-1 by hypothiocyanite: A post-translational control system in search of a role. *PLoS One*, **9**(11), e112797. https://doi.org/10.1371/journal.pone.0112797

Felton, J. S., & Knize, M. G. (1990). New mutagens from cooked food. *Progress in Clinical and Biological Research*, **347**, 19–38.

Final Report on the Safety Assessment of Benzaldehyde. (2006). *International Journal of Toxicology*, **25**(Suppl. 1), 11–27. https://doi.org/10.1080/10915810600716612

Frank, D., Piyasiri, U., Archer, N., Jenifer, J., & Appelqvist, I. (2018). Influence of saliva on individual in-mouth aroma release from raw cabbage (Brassica oleracea var. capitata f. rubra L.) and links to perception. *Heliyon*, **4**(12), e01045. https://doi.org/10.1016/j.heliyon.2018.e01045

Frumento, D. (2018). Oral bacteria contribution in wine flavor perception. *Current Trends in Biomedical Engineering & Biosciences*, **15**(5). https://doi.org/10.19080/ctbeb.2018.15.555923

Gamage, N., Barnett, A., Hempel, N., Duggleby, R. G., Windmill, K. F., Martin, J. L., & McManus, M. E. (2006). Human sulfotransferases and their role in chemical metabolism. *Toxicological Sciences*, **90**(1), 5–22. https://doi.org/10.1093/toxsci/kfj061

Gemert, L. J. V. (2003). *Flavour thresholds: Compilations of flavour threshold values in water and other media*. Oliemans Punter.
Chen, Y., Zhu, J. Y., Hong, K. H., Mikles, D. C., Georg, G. I., Goldstein, A. S., Amory, J. K., & Schonbrunn, E. (2018). Structural basis of ALDH1A2 inhibition by irreversible and reversible small molecule inhibitors. *ACS Chemical Biology*, **13**(3), 582–590. https://doi.org/10.1021/acschembio.7b00685

Chetyrkin, S. V., Belyaeva, O. V., Gough, W. H., & Kedishvili, N. Y. (2001). Characterization of a novel type of human microsomal 3alpha-hydroxysteroid dehydrogenase: Unique tissue distribution and catalytic properties. *Journal of Biological Chemistry*, **276**(25), 22278–22286. https://doi.org/10.1074/jbc.M102076200

Choi, J. Y., Stover, J. S., Angel, K. C., Chowdhury, G., Rizzo, C. J., & Guengerich, F. P. (2006). Biochemical basis of genotoxicity of heterocyclic arylamine food mutagens: Human DNA polymerase eta selectively produces a two-base deletion in copying the N2-guanyl adduct of 2-amino-3-methylimidazo[4,5-f]quinoline but not the C8 adduct at the NarI G3 site. *Journal of Biological Chemistry*, **281**(35), 25297–25306. https://doi.org/10.1074/jbc.M605699200

Cooper, A. J., Krasnikov, B. F., Niatsetskaya, Z. V., Pinto, J. T., Callery, P. S., Villar, M. T., Artigues, A., & Bruschi, S. A. (2011). Cysteine S-conjugate beta-lyases: Important roles in the metabolism of naturally occurring sulfur and selenium-containing compounds, xenobiotics and anticancer agents. *Amino Acids*, **41**(1), 7–27. https://doi.org/10.1007/s00726-010-0552-0

Cooper, A. J., & Pinto, J. T. (2006). Cysteine S-conjugate beta-lyases. *Amino Acids*, **30**(1), 1–15. https://doi.org/10.1007/s00726-005-0243-4

Corcos, L., Lucas, D., Le Jossic-Corcos, C., Dreano, Y., Simon, B., Plee-Gautier, E., Amet, Y., & Salaun, J. P. (2012). Human cytochrome P450 4F3: Structure, functions, and prospects. *Drug Metabolism and Drug Interactions*, **27**(2), 63–71. https://doi.org/10.1515/dmdi-2011-0037

Dahl, A. R., & Hadley, W. M. (1991). Nasal cavity enzymes involved in xenobiotic metabolism: Effects on the toxicity of inhalants. *Critical Reviews in Toxicology*, **21**(5), 345–372. https://doi.org/10.3109/10408449109019571

Dawes, C. (1969). The effects of flow rate and duration of stimulation on the concentrations of protein and the main electrolytes in human parotid saliva. *Archives of Oral Biology*, **14**(3), 277–294. http://www.sciencedirect.com/science/article/pii/000399699902313

Dawes, C., Pedersen, A. M., Villa, A., Ekstrom, J., Proctor, G. B., Vissink, A., Aframian, D., McGowan, R., Aliko, A., Narayana, N., Sia, Y. W., Joshi, R. K., Jensen, S. B., Kerr, A. R., & Wolff, A. (2015). The functions of human saliva: A review sponsored by the World Workshop on Oral Medicine VI. *Archives of Oral Biology*, **60**(6), 863–874. https://doi.org/10.1016/j.archoralbio.2015.03.004

Decker, M., Adamska, M., Cronin, A., Di Giallonardo, F., Burgener, J., Marowsky, A., Falck, JR, Morisseau, C, Hammock, BD, Gruzdev, A, Zeldin, DC, & Arand, M. (2012). EH3 (ABHD9): The first member of a new epoxide hydrolase family with high activity for fatty acid epoxides. *Journal of Lipid Research*, **53**(10), 2038–2045. https://doi.org/10.1194/jlr.M024448

Denny, P., Hagen, F. K., Hardt, M., Liao, L., Yan, W., Arellanno, M., Bassilian, S, Bedi, GS, Boontheung, P, Cociorva, D, Delahuuny, CM, Denny, T, Dunsmore, J, Faull, KF, Gilligan, J, Gonzalez-Begne, M, Halgand, F, Hall, SC, Han, X, . . . , & Fisher, S. J. (2008). The proteomes of human parotid and submandibular/sublingual gland salivas collected as the ductal secretions. *Journal of Proteome Research*, **7**(5), 1994–2006. https://doi.org/10.1021/pr700764j

Dinu, V., Kilic, A., Wang, Q., Ayed, C., Fadel, A., Harding, S. E., Yakubov, GE, & Fisk, I. D. (2020). Policy, toxicology and physico-chemical considerations on the inhalation of high concentrations of food flavour. *npj Science of Food*, **4**, 15. https://doi.org/10.1038/s41538-020-00075-y

Draganov, D. I., Teiber, J. F., Speelman, A., Osawa, Y., Sunahara, R., & La Du, B. N. (2005). Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. *Journal of Lipid Research*, **46**(6), 1239–1247. https://doi.org/10.1194/jlr.M400511-JLR200

Dufosse, L., Latrasse, A., & Spinnler, H.-E. (1994). Importance of lactones in food flavours: Structure, distribution, sensory properties and biosynthesis. *Sciences des Aliments*. **14**, 17–50. https://hal.archives-ouvertes.fr/hal-02637614

Edenberg, H. J., & McClintick, J. N. (2018). Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: A critical review. *Alcoholism, Clinical and Experimental Research*, **42**(12), 2281–2297. https://doi.org/10.1111/acer.13904

Endo, S., Matsunaga, T., Kitade, Y., Ohno, S., Tajima, K., El-Kabbani, O., & Hara, A. (2008). Human carbonyl reductase 4 is a mitochondrial NADPH-dependent quinone reductase. *Biochemical and Biophysical Research Communications*, **377**(4), 1326–1330. https://doi.org/10.1016/j.bbrc.2008.11.003

Endo, S., Miyagi, N., Matsunaga, T., Hara, A., & Ikari, A. (2016). Human dehydrogenase/reductase (SDR family) member 11 is a novel type of 17beta-hydroxysteroid dehydrogenase. *Biochemical and Biophysical Research Communications*, **472**(1), 231–236. https://doi.org/10.1016/j.bbrc.2016.01.190

Engeland, K., Hoog, J. O., Holmquist, B., Estonius, M., Jornvall, H., & Vallee, B. L. (1993). Mutation of Arg-115 of human class III alcohol dehydrogenase: A binding site required for formaldehyde dehydrogenase activity and fatty acid activation. *PNAS*, **90**(6), 2491–2494. https://doi.org/10.1073/pnas.90.6.2491

Fabrini, R., Bocedi, A., Camerini, S., Fusetti, M., Ottaviani, F., Pas-sali, F. M., Topazio, D., Iavarone, F, Francia, I, Castagnola, M, & Ricci, G. (2014). Inactivation of human salivary glutathione trans-ferase P1-1 by hypothiocyanite: A post-translational control system in search of a role. *PLoS One*, **9**(11), e112797. https://doi.org/10.1371/journal.pone.0112797

Felton, J. S., & Knize, M. G. (1990). New mutagens from cooked food. *Progress in Clinical and Biological Research*, **347**, 19–38.

Final Report on the Safety Assessment of Benzaldehyde. (2006). *International Journal of Toxicology*, **25**(Suppl. 1), 11–27. https://doi.org/10.1080/10915810600716612

Frank, D., Piyasiri, U., Archer, N., Jenifer, J., & Appelqvist, I. (2018). Influence of saliva on individual in-mouth aroma release from raw cabbage (Brassica oleracea var. capitata f. rubra L.) and links to perception. *Heliyon*, **4**(12), e01045. https://doi.org/10.1016/j.heliyon.2018.e01045

Frumento, D. (2018). Oral bacteria contribution in wine flavor perception. *Current Trends in Biomedical Engineering & Biosciences*, **15**(5). https://doi.org/10.19080/ctbeb.2018.15.555923

Gamage, N., Barnett, A., Hempel, N., Duggleby, R. G., Windmill, K. F., Martin, J. L., & McManus, M. E. (2006). Human sulfotransferases and their role in chemical metabolism. *Toxicological Sciences*, **90**(1), 5–22. https://doi.org/10.1093/toxsci/kfj061

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Hogg, D. M., & Jago, G. R. (1970). The oxidation of reduced nicotinamide nucleotides by hydrogen peroxide in the presence of lactoperoxidase and thiocyanate, iodide or bromide. *Biochemical Journal*, *117*(4), 791–797. https://doi.org/10.1042/bj1170791

Homann, N., Jousimies-Somer, H., Jokelainen, K., Heine, R., & Salaspuro, M. (1997). High acetaldehyde levels in saliva after ethanol consumption: Methodological aspects and pathogenetic implications. *Carcinogenesis*, *18*(9), 1739–1743. https://doi.org/10.1093/carcin/18.9.1739

Hsu, L. C., Chang, W. C., Shibuya, A., & Yoshida, A. (1992). Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in *Escherichia coli*. *Journal of Biological Chemistry*, *267*(5), 3030–3037.

Hussein, M. M., Kachikian, R., & Pidel, A. R. (1983). Analysis for flavor residuals in the mouth by gas chromatography. *Journal of Food Science*, *48*(6), 1884–1885. https://doi.org/10.1111/j.1365-2621.1983.tb05113.x

Ijichi, C., Wakabayashi, H., Sugiyama, S., Ihara, Y., Nogi, Y., Nagashima, A., Ihara, S., Niimura, Y., Shimizu, Y., Kondo, K., & Touhara, K. (2019). Metabolism of odorant molecules in human nasal/oral cavity affects the odorant perception. *Chemical Senses*, *44*(7), 465–481. https://doi.org/10.1093/chemse/bjz041

Ireland, L. S., Harrison, D. J., Neal, G. E., & Hayes, J. D. (1998). Molecular cloning, expression and catalytic activity of a human AKR7 member of the aldo-keto reductase superfamily: Evidence that the major 2-carboxybenzaldehyde reductase from human liver is a homologue of rat aflatoxin B1-aldehyde reductase. *Biochemical Journal*, *332*(Pt 1), 21–34. https://doi.org/10.1042/bj3320021

Jancova, P., Anzenbacher, P., & Anzenbacherova, E. (2010). Phase II drug metabolizing enzymes. *Biomedical papers of the Medical Faculty of Palacký University, Olomouc, Czech Republic*, *154*(2), 103–116. https://doi.org/10.5507/bp.2010.017

Kelson, T. L., Secor McVoy, J. R., & Rizzo, W. B. (1997). Human liver fatty aldehyde dehydrogenase: microsomal localization, purification, and biochemical characterization. *Biochimica Et Biophysica Acta*, *1335*(1–2), 99–110. https://doi.org/10.1016/s0304-4165(96)00126-2

Khanna, M., Chen, C. H., Kimble-Hill, A., Parajuli, B., Perez-Miller, S., Baskaran, S., Kim, J, Dria, K, Vasiliou, V, Mochly-Rosen, D, & Hurley, T. D. (2011). Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. *Journal of Biological Chemistry*, *286*(50), 43486–43494. https://doi.org/10.1074/jbc.M111.293597

Khanna, M., Qin, K. N., Wang, R. W., & Cheng, K. C. (1995). Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases. *Journal of Biological Chemistry*, *270*(34), 20162–20168. https://doi.org/10.1074/jbc.270.34.20162

Kida, H., Fukutani, Y., Mainland, J. D., de March, C. A., Vihani, A., Li, Y. R., Chi, Q, Toyama, A, Liu, L, Kameda, M, Yohda, M, & Matsunami, H. (2018). Vapor detection and discrimination with a panel of odorant receptors. *Nature Communications*, *9*(1), 4556. https://doi.org/10.1038/s41467-018-06806-w

Kikonyogo, A., & Pietruszko, R. (1996). Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma-aminobutyraldehyde: purification, characterization, cloning and distribution. *Biochemical Journal*, *316*(Pt 1), 317–324. https://doi.org/10.1042/bj3160317

Kivela, J., Parkkila, S., Parkkila, A. K., Leinonen, J., & Rajaniemi, H. (1999). Salivary carbonic anhydrase isoenzyme VI. *Journal of Physiology*, *520*(Pt 2), 315–320. https://doi.org/10.1111/j.1469-7793.1999.t01-1-00315.x

Kolm, R. H., Danielson, U. H., Zhang, Y. S., Talalay, P., & Mannervik, B. (1995). Isothiocyanates as substrates for human glutathione
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Heydel, J. M., Hanser, H. I., Faure, P., & Neiers, F. (2016). Odorant metabolizing enzymes in the peripheral olfactory process. In E. Guichard, C. Salles, M. Morzel and A.-M. Le Bon (Eds.), *Flavour* (pp. 34–56). John Wiley & Sons, Inc. https://doi.org/10.1002/9781118929384.ch2

Hodges, R. E., & Minich, D. M. (2015). Modulation of metabolic detoxification pathways using foods and food-derived components: A scientific review with clinical application. *Journal of Nutrition and Metabolism*, *2015*, 760689. https://doi.org/10.1155/2015/760689

Hogg, D. M., & Jago, G. R. (1970). The oxidation of reduced nicotinamide nucleotides by hydrogen peroxide in the presence of lactoperoxidase and thiocyanate, iodide or bromide. *Biochemical Journal*, *117*(4), 791–797. https://doi.org/10.1042/bj1170791

Homann, N., Jousimies-Somer, H., Jokelainen, K., Heine, R., & Salaspuro, M. (1997). High acetaldehyde levels in saliva after ethanol consumption: Methodological aspects and pathogenetic implications. *Carcinogenesis*, *18*(9), 1739–1743. https://doi.org/10.1093/carcin/18.9.1739

Hsu, L. C., Chang, W. C., Shibuya, A., & Yoshida, A. (1992). Human stomach aldehyde dehydrogenase cDNA and genomic cloning, primary structure, and expression in *Escherichia coli*. *Journal of Biological Chemistry*, *267*(5), 3030–3037.

Hussein, M. M., Kachikian, R., & Pidel, A. R. (1983). Analysis for flavor residuals in the mouth by gas chromatography. *Journal of Food Science*, *48*(6), 1884–1885. https://doi.org/10.1111/j.1365-2621.1983.tb05113.x

Ijichi, C., Wakabayashi, H., Sugiyama, S., Ihara, Y., Nogi, Y., Nagashima, A., Ihara, S., Niimura, Y., Shimizu, Y., Kondo, K., & Touhara, K. (2019). Metabolism of odorant molecules in human nasal/oral cavity affects the odorant perception. *Chemical Senses*, *44*(7), 465–481. https://doi.org/10.1093/chemse/bjz041

Ireland, L. S., Harrison, D. J., Neal, G. E., & Hayes, J. D. (1998). Molecular cloning, expression and catalytic activity of a human AKR7 member of the aldo-keto reductase superfamily: Evidence that the major 2-carboxybenzaldehyde reductase from human liver is a homologue of rat aflatoxin B1-aldehyde reductase. *Biochemical Journal*, *332*(Pt 1), 21–34. https://doi.org/10.1042/bj3320021

Jancova, P., Anzenbacher, P., & Anzenbacherova, E. (2010). Phase II drug metabolizing enzymes. *Biomedical papers of the Medical Faculty of Palacký University, Olomouc, Czech Republic*, *154*(2), 103–116. https://doi.org/10.5507/bp.2010.017

Kelson, T. L., Secor McVoy, J. R., & Rizzo, W. B. (1997). Human liver fatty aldehyde dehydrogenase: microsomal localization, purification, and biochemical characterization. *Biochimica Et Biophysica Acta*, *1335*(1–2), 99–110. https://doi.org/10.1016/s0304-4165(96)00126-2

Khanna, M., Chen, C. H., Kimble-Hill, A., Parajuli, B., Perez-Miller, S., Baskaran, S., Kim, J, Dria, K, Vasiliou, V, Mochly-Rosen, D, & Hurley, T. D. (2011). Discovery of a novel class of covalent inhibitor for aldehyde dehydrogenases. *Journal of Biological Chemistry*, *286*(50), 43486–43494. https://doi.org/10.1074/jbc.M111.293597

Khanna, M., Qin, K. N., Wang, R. W., & Cheng, K. C. (1995). Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3 alpha-hydroxysteroid dehydrogenases. *Journal of Biological Chemistry*, *270*(34), 20162–20168. https://doi.org/10.1074/jbc.270.34.20162

Kida, H., Fukutani, Y., Mainland, J. D., de March, C. A., Vihani, A., Li, Y. R., Chi, Q, Toyama, A, Liu, L, Kameda, M, Yohda, M, & Matsunami, H. (2018). Vapor detection and discrimination with a panel of odorant receptors. *Nature Communications*, *9*(1), 4556. https://doi.org/10.1038/s41467-018-06806-w

Kikonyogo, A., & Pietruszko, R. (1996). Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma-aminobutyraldehyde: purification, characterization, cloning and distribution. *Biochemical Journal*, *316*(Pt 1), 317–324. https://doi.org/10.1042/bj3160317

Kivela, J., Parkkila, S., Parkkila, A. K., Leinonen, J., & Rajaniemi, H. (1999). Salivary carbonic anhydrase isoenzyme VI. *Journal of Physiology*, *520*(Pt 2), 315–320. https://doi.org/10.1111/j.1469-7793.1999.t01-1-00315.x

Kolm, R. H., Danielson, U. H., Zhang, Y. S., Talalay, P., & Mannervik, B. (1995). Isothiocyanates as substrates for human glutathione
transferases—Structure-activity studies. *Biochemical Journal*, **311**,
453–459.

Kragelund, C., Hansen, C., Torpet, L. A., Nauntofte, B., Brosen, K.,
Pedersen, A. M., Buchwald, C, Therkildsen, MH, & Reibel, J.
(2008). Expression of two drug-metabolizing cytochrome P450-
enzymes in human salivary glands. *Oral Diseases*, **14**(6), 533–540.
https://doi.org/10.1111/j.1601-0825.2007.01415.x

Krajka-Kuźniak, V. (2003). The effects of tannic acid on cytochrome P450 and phase II enzymes in mouse liver and kidney. *Toxicology Letters*, **143**(2), 209–216. https://doi.org/10.1016/S0378-4274(03)00177-2

Krueger, S. K., & Williams, D. E. (2005). Mammalian flavin-
containing monooxygenases: structure/function, genetic poly-
morphisms and role in drug metabolism. *Pharmacology & Ther-
apeutics*, **106**(3), 357–387. https://doi.org/10.1016/j.pharmthera.
2005.01.001

Kumar, P., Singh, A., Kumar Kanaujia, S., & Pradhan, A. (2018).
Human saliva for oral precancer detection: A comparison of fluo-
rescence & stokes shift spectroscopy. *Journal of Fluorescence*, **28**(1),
419–426. https://doi.org/10.1007/s10895-017-2203-2

Kumari, V., Dyba, M. A., Holland, R. J., Liang, Y. H., Singh, S. V., & Ji, X. (2016). Irreversible inhibition of glutathione S-transferase by phenethyl isothiocyanate (PEITC), a dietary cancer chemopreventive phytochemical. *PLoS One*, **11**(9), e0163821. https://doi.org/10.1371/journal.pone.0163821

Laskar, A. A., Khan, M. A., Askari, F., & Younus, H. (2017). Thy-
moquinone binds and activates human salivary aldehyde dehy-
drogenase: Potential therapy for the mitigation of aldehyde tox-
icity and maintenance of oral health. *International Journal of
Biological Macromolecules*, **103**, 99–110. https://doi.org/10.1016/j.
ijbiomac.2017.04.112

Lazard, D., Zupko, K., Poria, Y., Nef, P., Lazarovits, J., Horn, S., Khen, M., & Lancet, D. (1991). Odorant signal termination by olfactory UDP glucuronosyl transferase. *Nature*, **349**(6312), 790–793.
https://doi.org/10.1038/349790a0

Lindqvist, L., & Augustinsson, K. B. (1975). Esterases in human saliva. *Enzyme*, **20**(5), 277–291.

Liska, D. J. (1998). The detoxification enzyme systems. *Alternative Medicine Review*, **3**(3), 187–198.

Liu, L., Von Vett, A., Zhang, N., Walters, K. J., Wagner, C. R., & Hanna, P. E. (2007). Arylamine N-acetyltransferases: Characterization of the substrate specificities and molecular interactions of environmental arylamines with human NAT1 and NAT2. *Chemical Research in Toxicology*, **20**(9), 1300–1308. https://doi.org/10.1021/tx7001614

Lv, X., Zhang, J. B., Hou, J., Dou, T. Y., Ge, G. B., Hu, W. Z., & Yang, L. (2019). Chemical probes for human UDP-glucuronosyltransferases: A comprehensive review. *Biotechnology Journal*, **14**(1), e1800002. https://doi.org/10.1002/biot.201800002

Mackie, D. A., & Pangborn, R. M. (1990). Mastication and its influence on human salivary flow and alpha-amylase secretion. *Physiology & Behavior*, **47**(3), 593–595. https://doi.org/10.1016/0031-9384(90)90131-m

Maga, J. A., & Katz, I. (1976). Lactones in foods. *CRC Critical Reviews in Food Science and Nutrition*, **8**(1), 1–56. https://doi.org/10.1080/10408397609527216

Mallery, S. R., Budendorf, D. E., Larsen, M. P., Pei, P., Tong, M., Holpuch, A. S., Larsen, PE, Stoner, GD, Fields, HW, Chan, KK, Ling, Y, & Liu, Z. (2011). Effects of human oral mucosal tissue,

saliva, and oral microflora on intraoral metabolism and bioactiva-
tion of black raspberry anthocyanins. *Cancer Prevention Research*,
4(8), 1209–1221. https://doi.org/10.1158/1940-6207.CAPR-11-0040

Mannervik, B., Board, P. G., Hayes, J. D., Listowsky, I., & Pearson,
W. R. (2005). Nomenclature for mammalian soluble glutathione
transferases. *Methods in Enzymology*, **401**, 1–8. https://doi.org/10.
1016/S0076-6879(05)01001-3

Manson, M. M. (1980). Epoxides—Is there a human health problem?
*Occupational and Environmental Medicine*, **37**(4), 317–336.

Marchitti, S. A., Orlicky, D. J., & Vasiliou, V. (2007). Expression and initial characterization of human ALDH3B1. *Biochemical and Bio-physical Research Communications*, **356**(3), 792–798. https://doi.org/10.1016/j.bbrc.2007.03.046

Mayr, C. M., Parker, M., Baldock, G. A., Black, C. A., Pardon, K. H., Williamson, P. O., Herderich, MJ, & Francis, I. L. (2014). Determination of the importance of in-mouth release of volatile phenol glycoconjugates to the flavor of smoke-tainted wines. *Journal of Agricultural and Food Chemistry*, **62**(11), 2327–2336. https://doi.org/10.1021/jf405327s

Mescher, M., & Haarmann-Stemmann, T. (2018). Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options. *Pharmacology & Therapeutics*, **187**, 71–87. https://doi.org/10.1016/j.pharmthera.2018.02.012

Miura, T., Nishinaka, T., & Terada, T. (2008). Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1. *Molecular and Cellular Biochemistry*, **315**(1–2), 113–121.
https://doi.org/10.1007/s11010-008-9794-5

Moore, R. J., Watts, J. T., Hood, J. A., & Burritt, D. J. (1999). Intra-
oral temperature variation over 24 hours. *European Journal of
Orthodontics*, **21**(3), 249–261. https://doi.org/10.1093/ejo/21.3.249

Moretti, A., Li, J., Donini, S., Sobol, R. W., Rizzi, M., & Garavaglia, S. (2016). Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD(+) and retinoic acid. *Scientific Reports*, **6**, 35710. https://doi.org/10.1038/srep35710

Morisseau, C., & Hammock, B. D. (2005). Epoxide hydrolases: mech-
anisms, inhibitor designs, and biological roles. *Annual Review of
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annurev.pharmtox.45.120403.095920

Morquecho-Campos, P., Bikker, F. J., Nazmi, K., de Graaf, K., Laine, M. L., & Boesveldt, S. (2020). A stepwise approach investigating salivary responses upon multisensory food cues. *Physiology & Behavior*, **226**, 113116. https://doi.org/10.1016/j.physbeh.2020.113116

Muñoz-González, C., Brulé, M., Feron, G., & Canon, F. (2019). Does interindividual variability of saliva affect the release and metabolization of aroma compounds ex vivo? The particular case of elderly suffering or not from hyposalivation. *Journal of Texture Studies*, **50**(1), 36–44. https://doi.org/10.1111/jtxs.12382

Muñoz-González, C., Brulé, M., Martin, C., Feron, G. & Canon, F. (2021). Molecular mechanisms of aroma persistence: From noncovalent interactions between aroma compounds and oral mucosa to metabolization of aroma compounds by saliva and oral cells. ChemRxiv. Cambridge: Cambridge Open Engage; 2021; This content is a preprint and has not been peer-reviewed. https://doi.org/10.26434/chemrxiv.14595606.v1

Muñoz-González, C., Cueva, C., Angeles Pozo-Bayon, M., & Victoria Moreno-Arribas, M. (2015). Ability of human oral microbiota to produce wine odorant aglycones from odourless grape glycosidic
transferases—Structure-activity studies. *Biochemical Journal*, **311**,
453–459.

Kragelund, C., Hansen, C., Torpet, L. A., Nauntofte, B., Brosen, K.,
Pedersen, A. M., Buchwald, C, Therkildsen, MH, & Reibel, J.
(2008). Expression of two drug-metabolizing cytochrome P450-
enzymes in human salivary glands. *Oral Diseases*, **14**(6), 533–540.
https://doi.org/10.1111/j.1601-0825.2007.01415.x

Krajka-Kuźniak, V. (2003). The effects of tannic acid on cytochrome P450 and phase II enzymes in mouse liver and kidney. *Toxicology Letters*, **143**(2), 209–216. https://doi.org/10.1016/S0378-4274(03)00177-2

Krueger, S. K., & Williams, D. E. (2005). Mammalian flavin-
containing monooxygenases: structure/function, genetic poly-
morphisms and role in drug metabolism. *Pharmacology & Ther-
apeutics*, **106**(3), 357–387. https://doi.org/10.1016/j.pharmthera.
2005.01.001

Kumar, P., Singh, A., Kumar Kanaujia, S., & Pradhan, A. (2018).
Human saliva for oral precancer detection: A comparison of fluo-
rescence & stokes shift spectroscopy. *Journal of Fluorescence*, **28**(1),
419–426. https://doi.org/10.1007/s10895-017-2203-2

Kumari, V., Dyba, M. A., Holland, R. J., Liang, Y. H., Singh, S. V., & Ji, X. (2016). Irreversible inhibition of glutathione S-transferase by phenethyl isothiocyanate (PEITC), a dietary cancer chemopreventive phytochemical. *PLoS One*, **11**(9), e0163821. https://doi.org/10.1371/journal.pone.0163821

Laskar, A. A., Khan, M. A., Askari, F., & Younus, H. (2017). Thy-
moquinone binds and activates human salivary aldehyde dehy-
drogenase: Potential therapy for the mitigation of aldehyde tox-
icity and maintenance of oral health. *International Journal of
Biological Macromolecules*, **103**, 99–110. https://doi.org/10.1016/j.
ijbiomed.2017.04.112

Lazard, D., Zupko, K., Poria, Y., Nef, P., Lazarovits, J., Horn, S., Khen, M., & Lancet, D. (1991). Odorant signal termination by olfactory UDP glucuronosyl transferase. *Nature*, **349**(6312), 790–793.
https://doi.org/10.1038/349790a0

Lindqvist, L., & Augustinsson, K. B. (1975). Esterases in human saliva. *Enzyme*, **20**(5), 277–291.

Liska, D. J. (1998). The detoxification enzyme systems. *Alternative Medicine Review*, **3**(3), 187–198.

Liu, L., Von Vett, A., Zhang, N., Walters, K. J., Wagner, C. R., & Hanna, P. E. (2007). Arylamine N-acetyltransferases: Characterization of the substrate specificities and molecular interactions of environmental arylamines with human NAT1 and NAT2. *Chemical Research in Toxicology*, **20**(9), 1300–1308. https://doi.org/10.1021/tx7001614

Lv, X., Zhang, J. B., Hou, J., Dou, T. Y., Ge, G. B., Hu, W. Z., & Yang, L. (2019). Chemical probes for human UDP-glucuronosyltransferases: A comprehensive review. *Biotechnology Journal*, **14**(1), e1800002. https://doi.org/10.1002/biot.201800002

Mackie, D. A., & Pangborn, R. M. (1990). Mastication and its influence on human salivary flow and alpha-amylase secretion. *Physiology & Behavior*, **47**(3), 593–595. https://doi.org/10.1016/0031-9384(90)90131-m

Maga, J. A., & Katz, I. (1976). Lactones in foods. *CRC Critical Reviews in Food Science and Nutrition*, **8**(1), 1–56. https://doi.org/10.1080/10408397609527216

Mallery, S. R., Budendorf, D. E., Larsen, M. P., Pei, P., Tong, M., Holpuch, A. S., Larsen, PE, Stoner, GD, Fields, HW, Chan, KK, Ling, Y, & Liu, Z. (2011). Effects of human oral mucosal tissue,

saliva, and oral microflora on intraoral metabolism and bioactiva-
tion of black raspberry anthocyanins. *Cancer Prevention Research*,
4(8), 1209–1221. https://doi.org/10.1158/1940-6207.CAPR-11-0040

Mannervik, B., Board, P. G., Hayes, J. D., Listowsky, I., & Pearson,
W. R. (2005). Nomenclature for mammalian soluble glutathione
transferases. *Methods in Enzymology*, **401**, 1–8. https://doi.org/10.
1016/S0076-6879(05)01001-3

Manson, M. M. (1980). Epoxides—Is there a human health problem?
*Occupational and Environmental Medicine*, **37**(4), 317–336.

Marchitti, S. A., Orlicky, D. J., & Vasiliou, V. (2007). Expression and initial characterization of human ALDH3B1. *Biochemical and Bio-physical Research Communications*, **356**(3), 792–798. https://doi.org/10.1016/j.bbrc.2007.03.046

Mayr, C. M., Parker, M., Baldock, G. A., Black, C. A., Pardon, K. H., Williamson, P. O., Herderich, MJ, & Francis, I. L. (2014). Determination of the importance of in-mouth release of volatile phenol glycoconjugates to the flavor of smoke-tainted wines. *Journal of Agricultural and Food Chemistry*, **62**(11), 2327–2336. https://doi.org/10.1021/jf405327s

Mescher, M., & Haarmann-Stemmann, T. (2018). Modulation of CYP1A1 metabolism: From adverse health effects to chemoprevention and therapeutic options. *Pharmacology & Therapeutics*, **187**, 71–87. https://doi.org/10.1016/j.pharmthera.2018.02.012

Miura, T., Nishinaka, T., & Terada, T. (2008). Different functions between human monomeric carbonyl reductase 3 and carbonyl reductase 1. *Molecular and Cellular Biochemistry*, **315**(1–2), 113–121.
https://doi.org/10.1007/s11010-008-9794-5

Moore, R. J., Watts, J. T., Hood, J. A., & Burritt, D. J. (1999). Intra-
oral temperature variation over 24 hours. *European Journal of
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Pérez-Jiménez, M., Rocha-Alcubilla, N., & Pozo-Bayon, M. A. (2019). Effect of saliva esterase activity on ester solutions and possible consequences for the in-mouth ester release during wine intake. *Journal of Texture Studies*, **50**(1), 62–70. https://doi.org/10.1111/jtxs.12371

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Robert-Hazotte, A., Faure, P., Neiers, F., Potin, C., Artur, Y., Coureaud, G., & Heydel, J. M. (2019). Nasal mucus glutathione transferase activity and impact on olfactory perception and neonatal behavior. *Scientific Reports*, **9**(1), 3104. https://doi.org/10.1038/s41598-019-39495-6

Robert-Hazotte, A., Schoumacker, R., Semon, E., Briand, L., Guichard, E., Le Quere, J. L., Faure, P., & Heydel, J. M. (2019). Ex vivo real-time monitoring of volatile metabolites resulting from nasal odorant metabolism. *Scientific Reports*, **9**(1), 2492. https://doi.org/10.1038/s41598-019-39404-x

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Zhong, L., Liu, Z., Yan, R., Johnson, S., Zhao, Y., Fang, X., & Cao, D. (2009). Aldo-keto reductase family 1 B10 protein detoxifies dietary and lipid-derived alpha, beta-unsaturated carbonyls at physiological levels. *Biochemical and Biophysical Research Communications*, **387**(2), 245–250. https://doi.org/10.1016/j.bbrc.2009.06.123

Zviely, M. (2005). Aroma chemicals II: Heterocycles. *Chemistry and Technology of Flavors and Fragrances*, 85.D.J. Rowe (ed.). https://doi.org/10.1002/9781444305517.ch5

**How to cite this article:** Schwartz, M., Neiers, F., Charles, J. - P., Heydel, J. - M., Muñoz-González, C., Feron, G., & Canon, F. (2021). Oral enzymatic detoxification system: insights obtained from proteome analysis to understand its potential impact on aroma metabolization. *Compr Rev Food Sci Food Saf*, **20**, 5516–5547.
https://doi.org/10.1111/1541-4337.12857
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., Olsson, I., Edlund, K., Lundberg, E., Navani, S., Szigyarto, CA., Odeberg, J., Djureinovic, D., Takanen, JO, Hober, S, ..., & Pontén, F. (2015). Tissue-based map of the human proteome. *Science*, **347**(6220), 1260419. https://doi.org/10.1126/science.1260419

Václavíková, R., Hughes, D. J., & Souček, P. (2015). Microsomal epoxide hydrolase 1 (EPHX1): Gene, structure, function, and role in human disease. *Gene*, **571**(1), 1–8. https://doi.org/10.1016/j.gene.2015.07.071

Väkeväinen, S., Tillonen, J., Agarwal, D. P., Srivastava, N., & Salaspuro, M. (2000). High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deficient subjects: strong evidence for the local carcinogenic action of acetaldehyde. *Alcoholism, Clinical and Experimental Research*, **24**(6), 873–877.

Vondracek, M., Xi, Z., Larsson, P., Baker, V., Mace, K., Pfeifer, A., Tjälve, H, Donato, MT, Gomez-Lechon, MJ, & Grafstrom, R. C. (2001). Cytochrome P450 expression and related metabolism in human buccal mucosa. *Carcinogenesis*, **22**(3), 481–488. https://doi.org/10.1093/carcin/22.3.481

Walle, T., Browning, A. M., Steed, L. L., Reed, S. G., & Walle, U. K. (2005). Flavonoid glucosides are hydrolyzed and thus activated in the oral cavity in humans. *The Journal of Nutrition*, **135**(1), 48–52. https://doi.org/10.1093/jn/135.1.48

Weinshilboum, R. M., Otterness, D. M., & Szumlanski, C. L. (1999). Methylation pharmacogenetics: Catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. *Annual Review of Pharmacology and Toxicology*, **39**, 19–52. https://doi.org/10.1146/annurev.pharmtox.39.1.19

Winter, G., Van Der Westhuizen, T., Higgins, V. J., Curtin, C., & Ugliano, M. (2011). Contribution of cysteine and glutathione conjugates to the formation of the volatile thiols 3-mercaptohexan-1-ol (3MH) and 3-mercaptohexyl acetate (3MHA) during fermentation by Saccharomyces cerevisiae. *Australian Journal of Grape and Wine Research*, **17**(2), 285–290. https://doi.org/10.1111/j.1755-0238.2011.00127.x

Wu, F., Melis, R., McMillin, G. A., & Johnson-Davis, K. L. (2019). Retrospective data analysis of the influence of age and sex on TPMT activity and its phenotype-genotype correlation. *The Journal of Applied Laboratory Medicine*, **3**(5), 827–838. https://doi.org/10.1373/jalm.2018.027276

Xiao, T., Shoeb, M., Siddiqui, M. S., Zhang, M., Ramana, K. V., Srivastava, S. K., Vasiliou, V., & Ansari, N. H. (2009). Molecular cloning and oxidative modification of human lens ALDH1A1: implication in impaired detoxification of lipid aldehydes. *Journal of Toxicology and Environmental Health. Part A*, **72**(9), 577–584. https://doi.org/10.1080/15287390802706371

Yamahara, H., & Lee, V. H. L. (1993). Drug metabolism in the oral cavity. *Advanced Drug Delivery Reviews*, **12**(1), 25–39. https://doi.org/10.1016/0169-409X(93)90039-7

Younus, H., Arsalan, A., & Alam, M. F. (2020). Arsenic inhibits human salivary aldehyde dehydrogenase: Mechanism and a population-based study. *Chemosphere*, **243**, 125358. https://doi.org/10.1016/j.chemosphere.2019.125358

Zaccone, E. J., Goldsmith, W. T., Shimko, M. J., Wells, J. R., Schwegler-Berry, D., Willard, P. A., Case, SL, Thompson, JA, & Fedan, J. S. (2015). Diacetyl and 2,3-pentanedione exposure of human cultured airway epithelial cells: Ion transport effects and metabolism of butter flavoring agents. *Toxicology and Applied Pharmacology*, **289**(3), 542–549. https://doi.org/10.1016/j.taap.2015.10.004

Zemanova, L., Kirubakaran, P., Pato, I. H., Stambergova, H., & Vondrasek, J. (2017). The identification of new substrates of human DHRS7 by molecular modeling and in vitro testing. *International Journal of Biological Macromolecules*, **105**(Pt 1), 171–182. https://doi.org/10.1016/j.ijbiomac.2017.07.012

Zemanova, L., Navratilova, H., Andrys, R., Sperkova, K., Andrejs, J., Kozakova, K., Meier, M, Möller, G, Novotná, E, Šafr, M, Adamski, J, & Wsol, V. (2019). Initial characterization of human DHRS1 (SDR19C1), a member of the short-chain dehydrogenase/reductase superfamily. *Journal of Steroid Biochemistry and Molecular Biology*, **185**, 80–89. https://doi.org/10.1016/j.jsbmb.2018.07.013

Zhang, Y., Dufort, I., Rheault, P., & Luu-The, V. (2000). Characterization of a human 20alpha-hydroxysteroid dehydrogenase. *Journal of Molecular Endocrinology*, **25**(2), 221–228. https://doi.org/10.1677/jme.0.0250221

Zhong, L., Liu, Z., Yan, R., Johnson, S., Zhao, Y., Fang, X., & Cao, D. (2009). Aldo-keto reductase family 1 B10 protein detoxifies dietary and lipid-derived alpha, beta-unsaturated carbonyls at physiological levels. *Biochemical and Biophysical Research Communications*, **387**(2), 245–250. https://doi.org/10.1016/j.bbrc.2009.06.123

Zviely, M. (2005). Aroma chemicals II: Heterocycles. *Chemistry and Technology of Flavors and Fragrances*, 85.D.J. Rowe (ed.). https://doi.org/10.1002/9781444305517.ch5

**How to cite this article:** Schwartz, M., Neiers, F., Charles, J. - P., Heydel, J. - M., Muñoz-González, C., Feron, G., & Canon, F. (2021). Oral enzymatic detoxification system: insights obtained from proteome analysis to understand its potential impact on aroma metabolization. *Compr Rev Food Sci Food Saf*, **20**, 5516–5547.
https://doi.org/10.1111/1541-4337.12857