Research ArticlesModulation of Hepatic Cytochrome P450 during Listeria Monocytogenes Infection of the Brain
Section snippets
INTRODUCTION
Generalized inflammation and viral, bacterial, and parasitic infections have widely been shown to modulate cytochrome P450 expression and activity in the liver, lung, intestine, kidney, and other organs of several species including humans.1., 2., 3., 4., 5. In most but not all cases, this alteration is manifested as a depression in protein content via pretranslational mechanisms, and results in altered drug and endogenous substrate metabolism.1,5 The elimination of a number of drugs (e.g.,
Chemicals
Brain Heart Infusion Broth (BHI) was purchased from Becton Dickinson Microbiology Systems (Cockeysville, MD). All other chemicals were purchased from Sigma Chemical Company (St. Louis, MO). Frozen aliquots of L. monocytogenes (serotype 4b) were provided by Dr. Rafael Garduño (Microbiology Department, Dalhousie University). The 5% Trypsin Soy Agar blood plates used for bacterial culture were purchased from the Microbiology Laboratory at the Queen Elizabeth II Health Sciences Centre (Halifax,
L. Monocytogenes Infection and Bacterial Load in Brain and Liver
A dose of 5 × 102 CFU of L. monocytogenes injected into the lateral ventricle of the brain produced a nonlethal infection, and no severe morbidity was observed throughout the duration of these experiments. The rats injected with L. monocytogenes, however, had signs of lethargy, decreased social interaction, decreased grooming, and a slight weight loss. The time course of the infection was monitored by measuring the number of bacteria present in the brain and liver during the first 72 h after
DISCUSSION
It has now been established that systemic inflammation and infections can trigger a mechanism resulting in a direct or indirect alteration in cytochrome P450 forms and their corresponding activities.1,5 This results in changes in the capacity of the liver to metabolize drugs and chemicals and has a profound effect on the pharmacokinetics of certain drugs. Hepatic P450 regulation also seems to be compromised during inflammatory responses originating in the brain.5., 6., 7. The mechanism
CONCLUSIONS
These experiments show for the first time that a live bacterial infection largely confined to the CNS modulates cytochrome P450 enzymes in the liver of the rat. The loss of enzyme in the liver is time and bacterial load dependent, which reflects the dynamic nature not only of disease, but also of the concomitant regulation of cytochrome P450 enzymes that follows. The observation that total hepatic cytochrome P450 content was significantly lowered 48 h after infection implies that other isoforms,
Acknowledgements
The authors thank Rafael and Elizabeth Garduño for kindly providing the L. monocytogenes strain, as well as their expertise and patience. E. Garcia del Busto Cano was a recipient of a Killam Trusts studentship. This work was supported by the Canadian Institute of Health Research (CIHR). A portion of this work was presented in abstract form at the ASBMB/ASPET/FPS/PSC 2000 joint meeting in Boston, MA.
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