Correlation of in vitro and in vivo effects of gold compounds on leukocyte function: possible mechanisms of action

J Lab Clin Med. 1982 Jul;100(1):37-44.

Abstract

The anti-inflammatory effects of gold compounds include suppression of PMN lysosomal enzyme release. Since lysosomal products can provoke PMN aggregation, we assessed the effect of two gold compounds, auranofin and GST, on suppressing aggregation, degranulation, and metabolic functions of the cells. Aggregation of 1 x 10(7) cytochalasin B-treated PMNs in response to 2 x 10(-7)M FMLP, as assessed by light scattering, was inhibited in a dose-dependent fashion by both drugs. Concentrations of auranofin ranging from 5 to 20 microM caused 30.8% to 89% inhibition, whereas 200 microM GST reduced aggregation by only 32%. FCS or BSA added to suspensions of normal PMNs considerably reduced the gold compound inhibitory effect on PMN aggregation. Cell viability assessed by dye exclusion and lactate dehydrogenase release was unaffected by the drugs. The suppressive activities of the drugs could not be removed by washing the PMNs. Correspondingly, the drugs suppressed lysosomal enzyme release induced by FMLP of PMNs rendered secretory with cytochalasin B. Concentrations of 20 microM auranofin and 200 microM GST resulted, respectively, in a 61.5% and 19.3% reduction of release of lysozyme, 61.7% and 27.1% reduction of beta-glucuronidase, 84.8% and 33.7%s reduction of myeloperoxidase, and 50.0% and 25.0% reduction of lactoferrin. Furthermore, auranofin inhibited 14C-1-glucose oxidation through the hexose monophosphate shunt in response to stimulation by either PMA or methylene blue. The in vivo studies suggested that auranofin could prevent neither neutropenia induced by zymosan-activated serum nor a corresponding rise in plasma lactoferrin levels. These findings suggest that the beneficial effect of gold compounds in rheumatoid arthritis are unlikely to be related to their ability to dampen PMN activation in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Auranofin
  • Aurothioglucose / analogs & derivatives*
  • Aurothioglucose / antagonists & inhibitors
  • Aurothioglucose / pharmacology
  • Cell Aggregation / drug effects
  • Cells, Cultured
  • Cytochalasin B / pharmacology
  • Glucose / metabolism
  • Glucuronidase / metabolism
  • Gold / analogs & derivatives*
  • Gold Sodium Thiomalate / antagonists & inhibitors
  • Gold Sodium Thiomalate / pharmacology*
  • Humans
  • Lactoferrin / metabolism
  • Muramidase / metabolism
  • N-Formylmethionine / analogs & derivatives
  • N-Formylmethionine / pharmacology
  • N-Formylmethionine Leucyl-Phenylalanine
  • Neutrophils / drug effects*
  • Neutrophils / enzymology
  • Neutrophils / physiology
  • Oligopeptides / pharmacology
  • Peroxidase / metabolism
  • Rabbits

Substances

  • Anti-Inflammatory Agents
  • Oligopeptides
  • Gold Sodium Thiomalate
  • Aurothioglucose
  • Cytochalasin B
  • Auranofin
  • N-Formylmethionine
  • N-Formylmethionine Leucyl-Phenylalanine
  • Gold
  • Peroxidase
  • Muramidase
  • Glucuronidase
  • Lactoferrin
  • Glucose