Abstract
Numerous 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 the liver in 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 (CYP) 2A3 and 3A9, UDP-glucuronosyltransferase (UGT) 2A1 and multidrug resistance-related protein type 1) and increased UGT activities. Surprisingly, 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 in the OM, respectively. The transcription factors AhR, Nrf2, PPARα, PXR and GR were detected in the OM but no CAR 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.
- CYP gene regulation
- enzyme induction
- extrahepatic cytochrome P450
- glutathione transferases
- nuclear receptors
- sulfotransferases
- transporters
- UDP glucuronyltransferases
Footnotes
- Received June 18, 2010.
- Accepted July 16, 2010.
- The American Society for Pharmacology and Experimental Therapeutics