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 α, 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.
Footnotes
This work was supported by the Agence Nationale de la Recherche [Grant ANR-05-PNRA-1.E7 Aromalim].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.035014.
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- XME
- xenobiotic-metabolizing enzymes
- OM
- olfactory mucosa
- P450
- cytochrome P450
- ALDH
- aldehyde dehydrogenase
- EPHX
- epoxide hydrolase
- UGT
- UDP glucuronosyltransferase
- SULT
- sulfotransferase
- GST
- glutathione S-transferase
- MDR
- multidrug resistance protein
- MRP
- multidrug resistance-associated protein
- OAT
- organic anion transporter
- OCT
- organic cation transporter
- AR
- Aroclor 1234
- AhR
- aryl hydrocarbon receptor
- CAR
- constitutive androstane receptor
- PXR
- pregnane X receptor
- Nrf2
- nuclear factor E2-related factor 2
- MC
- 3-methylcholanthrene
- DEX
- dexamethasone
- O
- oil
- C
- control
- PB
- phenobarbital
- EQ
- ethoxyquin
- RT-PCR
- reverse transcriptase-quantitative polymerase chain reaction
- POD
- phenacetin-O-deethylase
- NO
- nifedipine oxidase
- CZX
- chlorzoxazone hydroxylase
- HPLC
- high-performance liquid chromatography
- EROD
- ethoxyresorufin-O-deethylase
- PROD
- pentoxyresorufin-O-dealkylase
- NQO1
- quinone reductase
- mGST
- glutathione S-transferase
- 4-MU
- 4-methylumbelliferone
- AOH3
- aldehyde oxidase homolog 3
- PNP
- p-nitrophenol
- PPAR
- peroxisome proliferator-activated receptor
- GR
- glucocorticoid receptor.
- Received June 18, 2010.
- Accepted July 16, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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