During infection and inflammation, the capacity of the liver to metabolize drugs is impaired due to a reduction in hepatic content of cytochrome P450 (CYP), which can render clinically important medications ineffective or toxic. Cytokines and chemokines contribute as blood borne mediators of this effect on the liver. However, the exact mechanism by which cytokines alter CYP is unknown. Upon infection, viruses take over cellular machinery for self-replication and survival from the time the virus binds to receptors on the cell surface. Integrins, heterodimeric proteins expressed on all nucleated cells, serve as a site of entry for various pathogens. They also initiate signals inside the cell to regulate gene transcription, cell proliferation and survival. Studies of CYP expression in primary cultures of rat and human hepatocytes suggest that integrins influence CYP expression and function. The objective of this study is to investigate mechanisms of long-term virus-induced alterations in drug metabolism, using recombinant adenoviral vectors as prototype pathogens. The hypothesis being tested is that interaction of viral proteins with integrin receptors is responsible for changes of hepatic CYP gene expression and function. Capsid protein effects will be assessed by treating rats with either a """"""""gutted"""""""" virus with all viral genes deleted, PEGylated virus which does not interact with integrin receptors, UV inactivated or wild type virus. We will also determine if changes in CYP by these agents is achieved by transcriptional, posttranscriptiontional or postranslational mechanisms in vivo and in macrophage free primary cultures of rat hepatocytes to rule out cytokine effects. This hypothesis has not been tested and could have significant impact on current thought on regulation of CYP gene expression. This is of vast importance as cases of viral infection escalate in the general population and viruses are used as medicinal agents for gene therapy and vaccination protocols. Results from these studies could lead to the development of new anti-viral agents, identification of genetic markers to screen patients for potential aberrations in drug metabolism, and possibly to methods to mitigate drug-induced toxicity during viral infection and design of safer retargeted viruses for therapeutic applications. ? ?
