Olfactory acuity is dependent upon the efficient processing and clearance of potentially toxic substance from the nasal cavity. A compromise in expression or activity of nasal detoxifying enzymes could result in disease and infection, leading to loss of function. An olfactory-specific cytochrome P450 isoform, P450 2G1, is localized in sustentacular cells and Bowman's glands of the olfactory mucosa, suggesting a unique role in olfactory function. The regulatory mechanisms of P450 2G1 expression are unknown. However, P450 2G1 down-regulation occurs during periods of neuronal trauma. Recent in vivo evidence from hepatic systems shows that acute phase response and localized inflammatory reaction lead to the production of reactive oxygen species (ROS) that negatively influence the expression and activity of liver P450s. Observations in olfactory tissue indicate that nitric oxide synthase (NOS) and a superoxide dismutase (SOD) enzymes are up-regulated in abnormal olfactory mucosa. We have reported that such conditions correlate with a loss of P450 2G1 expression. We hypothesize that ROS mediate the suppression of P450 2G1 during olfactory trauma in the mouse. In support of this hypothesis, we present preliminary data showing that induction of the acute phase response results in decreased olfactory P450 activity, and decreased expression of P450 2G1 protein. In addition, we demonstrate that P450 2G1 mRNA is creased in the traumatized olfactory mucosa. Our objectives are: 1) to characterize the expression and activity of P450 2G1, NOS, and SOD enzymes in the olfactory mucosa during trauma and the acute phase response; 2) to identify nitrotyrosines ( a marker of oxidative stress) during these stages; 3) determine the ability of NOS inhibitors to attenuate the effect of immunomodulatory agents; and 4) to determine the ability of NOS inhibitors to attenuate the effect of immunomodulatory agents; and 4) to determine whether the acute phase response causes altered DNA binding activity at potential regulatory regions of the CYP2G1 promoter. In summary, this study will determine how cytokines and ROS influence gene expression, namely cytochrome P450, in detoxifying cells of the olfactory system. Indeed, decreased olfactory acuity has been noted following infection in the nasal cavity. Thus, determining how olfactory tissue adapts to immune response mechanisms has direct relevance to olfactory performance during systemic infection and conditions such as upper respiratory disease in humans.
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