This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Elucidating the mechanisms of oxidative transformation of xenobiotics by nitric oxide-derived oxidants (NOx) and the formation of electrophilic intermediates are the primary focus of the proposed investigation. The three major species of NOx, namely, nitrogen dioxide, carbonate radical, and peroxynitrite represent an important class of oxidants that are produced during the down regulation of nitric oxide in biological environments. It is our hypothesis that NOx cause oxidative transformation and metabolite activation of xenobiotics, thereby contributing to cellular oxidant stress. We envision two different scenarios that can explain oxidative transformation of xenobiotics. Some xenobiotics that contain a hetero atom (N, S, or P) in its low oxidation state can undergo oxidative transformation by NOx directly, while others require prior metabolism by enzymes of the cytochrome P450 system (CYP 450), flavin monooxygenases (FMOs), or myeloperoxidase (MPO). To address these divergent situations, the study is divided into two parts. In the first part, we will examine the direct reactions of NOx with xenobiotics (Specific Aim 1). In the second part, we will study the reactions of NOx with xenobiotic metabolites formed in reactions of xenobiotics with FMOs, MPOs, and CYP 450 (Specific Aim 2). We will employ CYP 450 that are either consitutive or induced by Aroclor 1254, 3-methylcholanthrene, or phenobarbital. In both specific aim 1 and 2, emphasis will be placed on the formation of small but significant yields of electrophilic intermediates that are capable of binding DNA and other macromolecules or have the ability to cause depletion of cellular antioxidants. Oxidative biotransformation of xenobiotics resulting in the formation of electrophilic intermediates by NOx may provide newer avenues for understanding the mechanism of toxicity induced by environmental pollutants and pharmaceuticals. The proposed study will add to a further understanding of the long-term toxicological consequences of NOx-xenobiotic interactions and specifically their role in establishment of cellular oxidative stress.
Showing the most recent 10 out of 179 publications
