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Nitric oxide is a mediator of the decrease in cytochrome P450-dependent metabolism caused by immunostimulants

O G Khatsenko1, S S Gross, A B Rifkind

  • 1William Harvey Research Institute, St. Bartholomew's Medical College, London, England.

Proceedings of the National Academy of Sciences of the United States of America
|December 1, 1993
PubMed
Summary

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Bacterial lipopolysaccharide (LPS) suppresses liver metabolism by inhibiting cytochrome P450 enzymes. This study shows nitric oxide (NO) overproduction is a key mechanism behind LPS-induced P450 suppression.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Toxicology

Background:

  • Immunostimulants, including bacterial lipopolysaccharide (LPS), are known to suppress hepatic metabolism.
  • The mechanism by which immunostimulants reduce the activity of the hepatic cytochrome P450 mixed-function oxidase system has remained unclear.
  • Recent findings indicate that immunostimulants induce nitric oxide (NO) overproduction.

Purpose of the Study:

  • To investigate the role of NO overproduction in LPS-induced suppression of hepatic metabolism.
  • To determine if NO directly inhibits cytochrome P450 activity.

Main Methods:

  • In vitro incubation of rat and chicken hepatic microsomes with NO donors or nitric oxide synthase.
  • Spectral analysis of cytochrome P450 heme interaction with NO.

Related Experiment Videos

  • In vivo administration of LPS to rats and assessment of liver microsomal P450 activity and CO binding.
  • Treatment with a selective NO synthase inhibitor (N omega-nitro-L-arginine methyl ester).

    • Main Results:

    • In vitro exposure to NO significantly suppressed cytochrome P450-dependent oxygenation reactions in hepatic microsomes from both rat and chicken species.
    • NO was found to react with both Fe(2+) and Fe(3+) hemes of cytochrome P450 in vitro.
    • In vivo, LPS administration reduced P450 activity and CO binding, which correlated positively with NO synthesis.
    • Inhibition of NO synthesis largely prevented LPS-induced decreases in P450 activity and CO binding.

    Conclusions:

    • Nitric oxide (NO) overproduction is a significant mediator of the suppression of hepatic metabolism induced by bacterial lipopolysaccharide (LPS).
    • NO directly inhibits cytochrome P450 activity by interacting with its heme component.
    • Targeting NO synthesis may offer a therapeutic strategy to mitigate LPS-induced metabolic dysfunction.