Effects of Typical Inducers on Olfactory Xenobiotic-Metabolizing Enzyme, Transporter, and Transcription Factor Expression in Rats

Abstract

ABSTRACT:Several xenobiotic-metabolizing enzymes (XMEs) have been identified in the olfactory mucosa (OM) of mammals. However, the molecular mechanisms underlying the regulation of these enzymes have been little explored. In particular, information on the expression of the transcriptional factors in this tissue is quite limited. The aim of the present study was to examine the impact of five typical inducers, Aroclor 1254, 3-methylcholanthrene, dexamethasone, phenobarbital, and ethoxyquin, on the activities and mRNA expression of several XMEs in the OM and in the liver of rats. We also evaluated the effects of these treatments on the mRNA expression of transcription factors and transporters. On the whole, the intensities of the effects were lower in the OM than in the liver. Dexamethasone was found to be the most efficient treatment in the OM. Dexamethasone induced the transcription of several olfactory phase I, II, and III genes [such as cytochromes P450 2A3 and 3A9, UDP-glucuronosyltransferase (UGT) 2A1, and multidrug resistance-related protein type 1] and increased UGT activities. We observed that dexamethasone up-regulated sulfotransferase 1C1 expression in the OM but down-regulated it in the liver. Aroclor and ethoxyquin induced the gene expression of CYP1A and quinone reductase, respectively, in the OM. The transcription factors aryl hydrocarbon receptor, nuclear factor E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor ␣, pregnane X receptor, and glucocorticoid receptor were detected in the OM, but no constitutive androstane receptor expression was observed. Dexamethasone and Aroclor enhanced olfactory Nrf2 expression. These results demonstrate that olfactory XME can be modulated by chemicals and that the mechanisms involved in the regulation of these enzymes are tissue-specific.

Functional Evidence of Multidrug Resistance Transporters (MDR) in Rodent Olfactory Epithelium

“…Recent studies have detected the presence of mRNA of MRP1, MRP3, MRP4, and MRP5 in adult rat OE [14], [19], [20], [33], but no data are avaible for the OE of mouse or newborn rodents. Our RT-PCR results show that both Pgp encoding genes mdr1a and mdr1b as well MRP1 are expressed in OE of newborn and adult animals of both species.…”

“…Also a very robust immunolocalization of MRP1 to sustentacular cells of the rat OE has recently been shown by Kudo et al [19]. Further expression of MRP1, MRP3, MRP 4 and MRP 5 has been reported in the olfactory epithelium of rat [14], [19], [20]. The few functional MDR activity tests in OE of mammals have focused on Pgp transport activity across excised olfactory tissue or whole animals, and so far no functional test for MRP1 has been performed.…”

Lack of TRPM5-Expressing Microvillous Cells in Mouse Main Olfactory Epithelium Leads to Impaired Odor-Evoked Responses and Olfactory-Guided Behavior in a Challenging Chemical Environment

“…Second, the MOE serves as an epithelial surface barrier, preventing or minimizing inhaled xenobiotics, such as air pollutants and infectious agents, from entering the brain, where they can create inflammation and neurodegeneration (Prediger et al, 2006; Imamura and Hasegawa-Ishii, 2016). Third, the MOE serves as a primary site for metabolizing and removing xenobiotics in the upper respiratory tract (Chen et al, 1992; Thornton-Manning et al, 1997; Thiebaud et al, 2010). The MOE is susceptible to xenobiotic insults owing to its large surface area and direct contact with inhaled chemicals.…”

Manipulation of olfactory tight junctions using papaverine to enhance intranasal delivery of gemcitabine to the brain

“…Transporter-mediated drug uptake involves a balance between efflux transporters such as MRPs 1, 3, 4 and 5; Pgp, and Bcrp, as well as influx transporters such as ENT1 and 2; many of these transporters have been localized in the rat OE (Genter et al, 2010; Kudo et al, 2010; Thiebaud et al, 2010; Agarwal et al, 2013). Studies have shown gemcitabine transport is mediated by hENT1, and rat ENT1 mediates gemcitabine translocation across the BBB (Thomas et al, 2008; Farrell et al, 2009).…”