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Factors involved in the depression of hepatic mixed function oxidase during infections with Listeria monocytogenes
1Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Abstract:
A number of infections are capable of depressing the capacity of the liver to metabolize drugs. We have studied a number of factors which could be involved in the depression of cytochrome P-450 and related drug biotransformation enzymes during infections with Listeria monocytogenes. During the course of the infection, drug metabolism and heme content of hepatic microsomes were depressed but heme oxygenase was elevated. A free radical scavenger alpha-tocopherol did not prevent the loss and xanthine oxidase activities did not correlate with the time course of the loss. Infections in susceptible (balb/c) mice produced a larger loss in drug metabolism than in resistant (C57BL/6) mice, and an avirulent strain of the bacteria was without effect. A preparation of hemolysin isolated from Listeria monocytogenes produced a dose-dependent loss of cytochrome P-450 in isolated hepatocytes. These experiments indicate that the loss of drug metabolism during Listeria infections is most likely due to hemolysin released by the bacteria.
Insights
Bacterial infections, like Listeria monocytogenes, can impair liver drug metabolism. This study found that bacterial hemolysin is the likely cause of reduced cytochrome P-450 activity during Listeria infections.
Area of Science:
- Pharmacology
- Microbiology
- Hepatology
Background:
- Infections can significantly alter liver function, impacting drug metabolism.
- Cytochrome P-450 enzymes are crucial for drug biotransformation and are susceptible to disruption.
- Listeria monocytogenes is a pathogen known to cause systemic infections.
Purpose of the Study:
- To investigate the mechanisms by which Listeria monocytogenes infection depresses hepatic drug metabolism.
- To identify specific factors responsible for the reduction in cytochrome P-450 and related enzymes.
Main Methods:
- Studied drug metabolism, heme content, and enzyme activities (heme oxygenase, xanthine oxidase) in infected mice.
- Compared infection effects in susceptible (balb/c) versus resistant (C57BL/6) mouse strains.
- Assessed the impact of isolated Listeria hemolysin on cytochrome P-450 in hepatocytes.
Main Results:
- Listeria infection led to depressed drug metabolism and decreased hepatic microsomal heme content.
- Heme oxygenase activity increased, while free radicals and xanthine oxidase did not correlate with the observed metabolic depression.
- Susceptible mice showed greater drug metabolism loss; an avirulent strain had no effect.
- Listeria hemolysin caused a dose-dependent decrease in cytochrome P-450 in isolated hepatocytes.
Conclusions:
- The depression of drug metabolism during Listeria infections is primarily attributed to hemolysin released by the bacteria.
- Bacterial hemolysin directly impacts hepatic cytochrome P-450 levels, leading to impaired drug metabolism.