The enzymes prostaglandin synthetase (PGS) and lipoxygenase can cooxidise a variety of xenobiotics to reactive intermediates during the metabolism of arachidonic acid (AA). PGS exhibited a gradient of activity within the kidney which was greatest in the papilla and least in the cortex. Rabbit and rat renal microsomes metabolised the model compound, tetramethylphenylenediamine (TMPD), in the presence of AA by pathways which were predominantly PGS and lipoxygenase-dependent, respectively. Therefore, both enxymes may play a role in the development of site-specific nephrotoxicity within the kidney. The model papillotoxin 2-bromoethanamine (2-BEA) which exhibits target selective toxicity for the renal papilla, was found to be significantly more toxic to medullary interstitial cells than to proximal tubule cells in culture. Toxicity was enhanced significantly by AA whereas inhibitors of cyclooxygenase (indomethacin, aspirin), prostaglandin hydroperoxidase (propylthiouracyl) and lipoxygenase (nordihydrogauaretic acid) all significantly decreased 2-BEA toxicity. This suggests that toxicity is mediated either by the hydroperoxidase component of PGS or by lipoxygenase. Thromboxane A<sub>2</sub> (TxA<sub>2</sub>) is thought to play a pivotal role in cyclosporin A (CsA) induced nephrotoxicity. Administration of a thromboxane synthetase inhibitor (TSI) normalised TxB<sub>2</sub> excretion but only partially protected against other factors involved. However, treatment with angiotensin converting enzyme inhibitor either alone or in combination with TSI did not affect CsA nephrotoxicity. Tubular toxicity, manifest as N-acetyl-β-D-glucosaminidase (NAG) enzymuria, glycosuria, vacuolation, calcification and chronic tubule damage, may contribute to the CsA-induced reduction in renal function. In addition to protecting against CsA-induced nephrotoxicity, the administration of TSI to CsA-treated rats also partially reversed pre-existing renal damage.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:481095 |
| Date | January 1990 |
| Creators | Cockburn, Elinor M. |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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