Nitric oxide-associated regulation of hepatocyte glutathione synthesis is a guanylyl cyclase-independent event.

Journal Article (Journal Article)

BACKGROUND: In a system of rat hepatocytes in primary culture, inhibition of cytokine-mediated nitric oxide (NO) production has been shown to be protective in states of oxidative stress. In the absence of oxidative injury, inhibition of NO synthesis has been associated with decreased intracellular levels of reduced glutathione. METHODS: To further characterize the role of NO in hepatocyte glutathione metabolism, cytokine-mediated NO synthesis was inhibited by addition of a competitive substrate inhibitor. Reduced glutathione, NO metabolites, and enzyme activity and steady-state mRNA levels of the rate-limiting enzyme for reduced glutathione (GSH) synthesis, gamma-glutamylcysteine synthetase, were determined in the presence and absence of the substrate inhibitor. A diffusible cyclic guanosine monophosphate (cGMP) analog, 8-bromo-cGMP, was added in selected instances to determine the potential role of soluble guanylyl cyclase in glutathione metabolism. RESULTS: Inhibition of cytokine-induced NO synthesis was associated with depletion of glutathione. These levels were restored in the presence of pharmacologic concentrations of a NO donor. Along with decreased glutathione levels, gamma-glutamylcysteine synthetase enzyme activity and steady state mRNA levels were also decreased with inhibition of NO synthesis. Addition of 8-bromo-cGMP did not alter glutathione content or gamma-glutamylcysteine synthetase enzyme activity and steady-state mRNA levels. CONCLUSIONS: In this system of cultured rat hepatocytes, cytokine-mediated NO synthesis may be protective in states of oxidative stress through regulation of glutathione synthesis.

Full Text

Duke Authors

Cited Authors

  • Kuo, PC; Abe, KY

Published Date

  • August 1996

Published In

Volume / Issue

  • 120 / 2

Start / End Page

  • 309 - 314

PubMed ID

  • 8751598

International Standard Serial Number (ISSN)

  • 0039-6060

Digital Object Identifier (DOI)

  • 10.1016/s0039-6060(96)80303-5


  • eng

Conference Location

  • United States