Research Articles
Modulation of Hepatic Cytochrome P450 during Listeria Monocytogenes Infection of the Brain

https://doi.org/10.1002/jps.10433Get rights and content

Abstract

Hepatic cytochrome P450 enzymes can be modulated during systemic infections. Inflammatory responses in the brain have also been shown to cause a significant decrease in the levels and activities of important cytochrome P450 isoforms in the liver. We determined some of the effects of central nervous system (CNS) Listeria monocytogenes infection on hepatic cytochrome P450 systems in rats. Intracerebroventricular injection of L. monocytogenes resulted in a time-dependent modulation of CYP1A, CYP2B, and CYP3A activities in the liver. Total hepatic cytochrome P450 content was significantly lowered 48 h after administration of the bacterium, and hepatic CYP1A and CYP2B activities were significantly altered 48 and 72 h after infection, respectively, whereas CYP3A activity and protein content were depressed 72 h after the insult. Bacterial load in the brain increased dramatically over a 72-h period, but the number of bacteria cultured from liver over this time period was relatively small. Therefore, an infection largely confined to the CNS in the rat results in abnormal activity levels of certain hepatic cytochrome P450 enzymes crucial in drug metabolism. If such a response also occurs in humans, this has the potential to produce serious complications with drug and endogenous substrate metabolism in patients with an infectious disease involving the CNS. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association.

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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