RT Journal Article
SR Electronic
T1 Effects of Typical Inducers on Olfactory Xenobiotic-Metabolizing Enzyme, Transporter, and Transcription Factor Expression in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1865
OP 1875
DO 10.1124/dmd.110.035014
VO 38
IS 10
A1 Nicolas Thiebaud
A1 Maud Sigoillot
A1 Joëlle Chevalier
A1 Yves Artur
A1 Jean-Marie Heydel
A1 Anne-Marie Le Bon
YR 2010
UL http://dmd.aspetjournals.org/content/38/10/1865.abstract
AB 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.