| dc.description | The cytochromes P450 represent a superfamily of heme-containing drug metabolizing enzymes found in the liver and in other tissues. The regulation of these enzymes is altered during conditions of infection and inflammation however the mechanisms leading to such changes remain largely unknown, with cytokines believed to play a role in this regulation. The objectives of this thesis were to examine potential mechanisms that protect against the downregulation of cytochrome P450 (P450) and to determine the mechanisms of P450 regulation during conditions of lipopolysaccharide (LPS)-induced inflammation. Based on the fact that norepinephrine has many anti-inflammatory properties, we chose to examine the potential effects of beta-adrenergic stimulation on CYP1A levels using an in vitro model of central nervous system (CNS) inflammation induced by incubating primary astrocytes with LPS. Our results demonstrate that the co-administration of beta-adrenergic receptor agonists with LPS to cultured astrocytes prevents the LPS-mediated reduction in CYP1A activity in part due to a reduction in TNFalpha. To outline the mechanisms by which LPS regulates P450 in vivo, we administered LPS either intracerebroventricularly or intraperitoneally and examined the mRNA expression of CYP1A1/2, CYP2B1/2, CYP2D5, and CYP2E1. We show that during CNS inflammation, LPS is detected in the serum as early as 15 minutes following its i.c.v. administration. The results indicate that various transcription factors such Nuclear Factor kappa B (NF-kappaB) play an important role in the regulation of P450 during LPS-induced inflammatory models. In addition, we show that the regulation of CYP2E1 during conditions of LPS-induced inflammation occur predominantly at a post-transcriptional level. | en_US |
