Identification of a novel tissue-specific transcriptional activating element in the olfactory mucosapredominant cyp2a3 gene

CYP2A3, a cytochrome P450 (P450) monooxygenase highly active toward many nasal toxicants as well as endogenous compounds, is expressed abundantly in the olfactory mucosa and, in trace amounts, in the lung, but not in any other rat tissues examined. To understand the mechanisms that dictate tissue-selective expression for this and other P450 genes, we have examined the 5'-flanking region of the CYP2A3 gene. DNase I footprinting analysis revealed a single protected region in a 300-bp probe (-255 to +58) with nuclear extracts from olfactory mucosa, but not from liver, lung, kidney, or brain. The tissuespecific binding was confirmed by gel-shift analysis. The core sequence of the binding site, named NPTA (nasal-rjredominant transcriptional activating) element, was identified and found to be essential for transcriptional activity of the CYP2A3 promoter in vitro. NPTA-binding proteins were detectable at day 1 and were much more abundant at day 8 than at day 60 after birth. Furthermore, the levels of the binding proteins decreased dramatically during chemically-induced degeneration of the olfactory epithelium, paralleling the disappearance of olfactory microsomal CYP2A3 protein, and rebounded to higher-man- pretreatment levels during recovery. Thus, we have identified a novel transcriptional activating element which may play a crucial role in the tissue-selective expression of the CYP2A3 gene in the olfactory mucosa.