| dc.contributor.author | Armstrong, Steven. | en_US |
| dc.date.accessioned | 2014-10-21T12:38:50Z | |
| dc.date.available | 1992 | |
| dc.date.issued | 1992 | en_US |
| dc.identifier.other | AAINN76699 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/55300 | |
| dc.description | In the past 15 years there has been remarkable interest in the interaction between the system that protects us from infectious disease and that which allows us to inactivate therapeutic agents and environmental chemicals. There have been numerous reports of significant alterations in drug metabolism during viral infections in humans that in some cases have had severe clinical consequences. It is now reasonably well established that this effect is the result of virus-induced interferon production and subsequent depression of hepatic cytochrome P450 levels. | en_US |
| dc.description | To date, there have been only five reports regarding the effect of active bacterial infections on cytochrome P450. In none of these reports was the mechanism involved determined. One of the bacteria that was shown to depress cytochrome P450 was Listeria monocytogenes and the focus of this study was to determine the mechanism by which this effect occurred. The primary objectives were to establish if the effect was direct on the hepatocyte or involved other cell types, to determine if the mechanism involved an inhibition of synthesis or a degradation of cytochrome P450 apoprotein, and to determine the role of the hemolysin (secreted by listeria) in the effect. | en_US |
| dc.description | The activity of numerous cytochrome P450 isozymes were reversibly depressed in hepatic microsomes isolated from mice infected in vivo with Listeria monocytogenes (strain 15U). The levels of two specific isozymes (cytochrome P450IA1 and P450IIC11) were shown to be depressed by a pretranslational mechanism that involved a selective loss of mRNA coding for the specific cytochrome P450 apoproteins. Listeria had no effect on total hepatic mRNA levels and livers isolated from infected mice did not show any significant histological change. | en_US |
| dc.description | Listeria significantly depressed hepatocyte ethoxyresorufin-O-dealkylase (EROD) and benzyloxyresorufin-O-dealkylase (BROD) activities after 24 hour incubations with liver cell cultures containing hepatocytes and nonparenchymal cells, demonstrating that the effect of listeria infection on cytochrome P450 is predominantly due to an interaction within the liver and does not require the influence of extrahepatic cells or factors. This depression of cytochrome P450-mediated metabolism in hepatocytes was the result of both a direct effect on the hepatocyte and an interaction of listeria with hepatic nonparenchymal cells. An avirulent strain of listeria (M3D) that does not secrete hemolysin, had no effect on cytochrome P450-mediated metabolism and suggested that the presence of the hemolysin is an essential component of the mechanism. | en_US |
| dc.description | The incidence of Listeria monocytogenes infection in the general population is low but, if the capacity of listeria to depress cytochrome P450 proves to be an effect that is common to many different types of bacterial infections, then more clinical reports in this regard are likely in the future. This study serves to emphasize the warning that drugs with narrow therapeutic indices should be administered with caution during infectious disease caused by bacteria as well as viruses. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 1992. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Toxicology. | en_US |
| dc.subject | Biology, Microbiology. | en_US |
| dc.subject | Health Sciences, Immunology. | en_US |
| dc.title | Pretranslational depression of hepatic cytochrome P450 during Listeria monocytogenes infection. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
