The present investigations were aimed at providing an empirical basis for implicating altered prostaglandin (PG) and thromboxane (TX) biosynthesis in the aberrant heme metabolism and erythrocyte membrane properties which have been found to exist in hereditary muscular dystrophy and ataxia. / Picomolar concentrations of PGE(,1) and PGE(,2) were shown to exert opposing, biphasic effects on osmotic fragility, the hemolytic response to ouabain (without any direct effect on cation-activated adenosine triphosphatases), and echinocyte transformation of normal human erythrocytes. Ex vivo erythrocyte porphyrin analysis pointed to a mild depression of erythropoiesis in dystrophic mice that responded to dietary polyunsaturated fatty acids. The discovery of a paraporphyria in patients with hereditary ataxia was extended to in vitro porphyrin studies using 3-acetylpyridine as an experimental model of ataxia. / Systematic pharmacological studies in a newly designed, serum-free liver cell culture model and in ovo, together with chromatographic-fluorometric PG analysis, established that a certain rate or pattern of PG biosynthesis was required for optimal induction of hepatic (delta)-aminolevulinate synthase and porphyrin-heme biosynthesis. Moreover, the dramatic accumulation of protoporphyrin caused by putative, selective inhibitors of thromboxane synthase, and the exacerbation of experimental porphyria by phospholipase inhibitors provided unique evidence for a physiological, regulatory role of PGs and possibly TXA(,2) in heme biosynthesis at the level of mitochondrial ferrochelatase activity. / Original data obtained about PG effects on heme biosynthesis and erythrocyte properties may prove useful in devising effective therapies and monitoring clinical responses in anemias, porphyrias and hematological aspects of neuromuscular disease.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.68575 |
| Date | January 1980 |
| Creators | Morgan, Reginald Owen. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy () |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 000112494, proquestno: AAINK52040, Theses scanned by UMI/ProQuest. |
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