Interleukin-1-induced nitric oxide production modulates glutathione synthesis in cultured rat hepatocytes.

Published

Journal Article

In cultured rat hepatocytes, we have previously demonstrated that inhibition of interleukin-1 (IL-1)-mediated nitric oxide (NO) synthesis is associated with depletion of intracellular reduced glutathione (GSH) in toxin-mediated oxidative injury. To further examine NO's effects on GSH metabolism in rat hepatocytes, IL-1-mediated NO synthesis was examined in the context of 1) cysteine, cystine, and methionine uptake; 2) gene transcription and enzyme activities for gamma-glutamylcysteine synthetase, the rate-limiting enzyme in GSH synthesis, glutathione reductase, and glutathione peroxidase; and 3) GSH and oxidized glutathione (GSSG) levels. Inhibition of NO synthesis decreased the GSH content and GSH/GSSG ratio in a guanylyl cyclase-independent fashion. Enzyme activity and steady-state levels of mRNA for gamma-glutamylcysteine synthetase were also depressed. Nuclear run-on analysis demonstrated ablation of gamma-glutamylcysteine synthetase gene transcription. Hepatocellular uptake of cysteine, cystine, and methionine was not altered. Activity and steady-state mRNA levels for glutathione reductase and glutathione peroxidase were not affected. These results indicate that IL-1-mediated NO synthesis regulates hepatocyte GSH synthesis through a mechanism that is dependent on transcriptional regulation of the rate-limiting enzyme in GSH synthesis. In the setting of oxidative stress and IL-1 exposure, hepatocyte synthesis of NO may be protective through regulation of GSH synthesis.

Full Text

Duke Authors

Cited Authors

  • Kuo, PC; Abe, KY; Schroeder, RA

Published Date

  • September 1996

Published In

Volume / Issue

  • 271 / 3 Pt 1

Start / End Page

  • C851 - C862

PubMed ID

  • 8843715

Pubmed Central ID

  • 8843715

International Standard Serial Number (ISSN)

  • 0002-9513

Digital Object Identifier (DOI)

  • 10.1152/ajpcell.1996.271.3.C851

Language

  • eng

Conference Location

  • United States