NITRIC-OXIDE AND NITRIC OXIDE-GENERATING COMPOUNDS INHIBIT HEPATOCYTE PROTEIN-SYNTHESIS

Hepatocytes are stimulated to produce nitric oxide (NO.) from L-arginine in response to conditioned Kupffer cell medium or a combination of cytokines. Associated with the production of NO. in hepatocytes, there is a profound decrease in total protein synthesis ([H-3]leucine incorporation). This report demonstrates that authentic NO. and the NO.-generating compound S-nitroso-N-acetylpenicillamine inhibit hepatocyte total protein synthesis in a reversible and concentration-dependent fashion. In parallel with the suppression of hepatocyte total protein synthesis, authentic NO. inhibits the production of two specific hepatocyte proteins, albumin and fibrinogen, without influencing the quantity of albumin mRNA. Although authentic NO. induces a rapid increase in cGMP levels in hepatocytes, the addition of the cGMP analog 8-bromoguanosine 3':5' cyclic monophosphate to unstimulated HC cultures does not reproduce the inhibition of total protein synthesis. These data show that NO. is the hepatocyte L-arginine metabolite that inhibits protein synthesis. Furthermore, these findings indicate that NO. does not inhibit hepatocyte protein synthesis solely through the activation of soluble guanylate cyclase but appears to affect a translational or posttranslational process.