Subcellular actions of non-steroidal anti-inflammatory drugs: Lysosome and prostaglandin studies.

  • A. J. Rose

Student thesis: Doctoral ThesisPhD

Abstract

The stabilization of lysosomal membranes and the inhibition of prostaglandin biosynthesis are two of the many proposed mechanisms whereby anti-inflammatory drugs may exert their therapeutic action. In this context, the subcellular actions of certain non-steroidal agents have been investigated using in vitro techniques. Under specific conditions, rat liver lysosomal membranes were stabilized by aspirin, ibuprofen, indomethacin, flurbiprofen and chloroquine as assessed by the release of free acid phosphatase or beta-glucuronidase. The lysosomal enzymes were not inhibited by the above agents at therapeutic doses. Attempts were made to extend these studies to the inflammatory important lysosomes of polymorphonucelar leucocytes but difficulties were encountered. Although both ibuprofen and flurbiprofen decreased the inflammatory response in adjuvant-induced arthritis in the rat, no correlation was observed between paw size and total paw lysosomal levels. Prostaglandin biosynthesis was investigated in preparations of rabbit renal medullae and bovine seminal vesicles using a radiochemical technique. The synthesis of radioactive PGE2 and PGF2alpha from labelled precursor, arachidonic acid, was inhibited by non-steroidal anti-inflammatory acids at low concentrations in dose related responses. The rank order of potency of the drugs on the prostaglandin synthetase systems paralleled their clinical effectivness as anti-inflammatory agents. Possible iso-enzymes of PG-synthetase were indicated by changes in relative potencies of indomethacin and flurbiprofen in the two systems investigated. A high speed supernatant fraction of rabbit renal medulla homogenates was found to inhibit the biosynthesis of labelled prostaglandins by microsomes of the kidney preparation at pH 8.0. This observation of a natural "inhibitor" of PG-synthetase is used to explain a double pH optima for activity of crude cell free homogenates of this tissue at pH 7.0 and pH 9.0. No prostaglandin biosynthesis was detected in active human rheumatoid synovial tissues; although extracts of human rheumatoid, but not normal, leucocytes did indicate a small amount of PG-synthetase activity, which was inhibited by 10-5M indomethacin in vitro. The significance of these findings in relation to inflammation and the development of anti-inflammatory drugs is discussed.
Date of Award1975
LanguageEnglish
Awarding Institution
  • University of Bath

Cite this

Subcellular actions of non-steroidal anti-inflammatory drugs: Lysosome and prostaglandin studies.
Rose, A. J. (Author). 1975

Student thesis: Doctoral ThesisPhD