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Title: Mechanisms of renal glomerular toxicity of an N-hydroxyurea 5-lipoxygenase inhibitor
Author: Morley, Timothy James
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2001
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The N-hydroxyurea derivative, ((E)-N-{3-[3-(4-fluorophenoxy) phenyl]-1-(R,S)-methylprop-2-enyl}-N-hydroxyurea), (70C), was being developed as a 5-lipoxygenase inhibitor for the treatment of asthma and was found cause severe glomerulopathy in the rat (Read et al, 1995). The lesion appeared to be of greater severity in female rats compared with male rats. The earliest changes detected in the kidney by transmission electron microscopy were noted in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process loss. In the more advanced lesion, the degree of foot process loss became more obvious and changes in the kidney tubules were seen by light microscopy. Shortly after the onset of foot process loss, decreases in total plasma protein and albumin and increases in plasma cholesterol and triglycerides, urea and creatinine were recorded. These changes, particularly the foot process loss, together with increased proteinuria, hypoalbuminaemia, hypercholersterolaemia and lipaemia, are all characteristic of "minimal change nephrotic syndrome". In order to assess a potential structure-activity relationship with drug-induced nephropathy the N-hydroxyurea derivative 70C and an N-hydroxamic acid analogue, ((E)-N-{3-[3-(4-fluorophenoxy) phenyl]-1-(R, S)-methylprop-2-enyl}-N-hydroxamic acid), (360C), were administered to rats. 70C and 360C were dosed to female Wistar rats at 100mg/lg p.o. daily for 7 days. All biochemical and morphological investigations showed that 360C-treated rats were similar to the control group suggesting that the hydroxyurea moiety of 70C is responsible, either directly or indirectly, for the induction of the nephrotic syndrome seen in rats. The major mechanisms underlying drug-induced nephrotic syndrome are immune-complex mediated, involve lipid mediators, (especially thromboxane A2), or are free radical mediated. The involvement of immune-complexes was discounted due to their absence in the kidney sections of 70C-treated rats when examined by electron microscpy. Also, the fact that the time-course of the 70C-induced glomerular lesion was a matter of days, as detected by marked increases in proteinuria, is far too rapid for immune-mediated lesions as they exhibit a latent period of weeks and often months.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available