Inflammation is a biological process that is involved in many human diseases, and is triggered after physical injury, infection, or any other disease changes that activates the immune response. In the United States the top ten causes of death include diseases with secondary inflammatory effects that lead to difficulties during the medical management of the patient. This project focuses on the direct role human cytochrome P450 4F (CYP4F) isoforms play in controlling the effects of inflammation signaling. The human CYP4F subfamily consists of 7 isoforms and has been shown to metabolize, via hydroxylation, active leukotriene and prostaglandin mediators rendering products unable to prompt inflammatory cascade events. In addition, our laboratory has shown that human CYP4F11 is able to metabolize a great variety of drugs normally used in treatment of patients with traumatic brain injury or other insults. Thus levels of expression of the CYP4Fs (especially in peripheral organs) may play a critical role in resolution of inflammation as well as the efficacy of therapeutic drugs targeted to specific organs. This research proposal has been developed to test the hypothesis that CYP4Fs play an important time dependent regulatory role in controlling inflammation in humans, via the metabolism of drugs and endogenous mediators, and more specifically, inflammation occurring after physical trauma. I will test this general hypothesis through three specific aims. 1. Establish expression levels of CYP4Fs in patients that have experienced traumatic injury/insult by quantifying mRNA and protein levels in postmortem lung, heart, liver, kidney, brain and spleen. 2. Elucidate the relationship between ethnicity, gender, or age and CYP4F expression levels to determine if they affect CYP4Fs ability to resolve inflammation after traumatic injury/insult. 3. Determine each CYP4F isoforms' catalytic activity towards anti-inflammatory treatment drugs, and eicosanoid signaling molecules to define the role of CYP4Fs in the resolution of inflammation. Relevance to Public Health: Inflammation occurs in a variety of human disease processes. Of importance, it complicates the recovery period of patients, including those who have suffered relatively minor trauma, by interfering with healing and medication metabolism. We propose that the Cytochrome P450 4F subfamily of enzymes lower inflammation and help the recovery of patients suffering from secondary side effects of inflammation. ? ? ? ?
| Bell, Jordan C; Strobel, Henry W (2012) Regulation of cytochrome P450 4F11 by nuclear transcription factor-?B. Drug Metab Dispos 40:205-11 |
