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Title: Human renal lipoxygenases : implications for papillary necrosis
Author: Stewart, Victoria C.
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1995
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The long-term administration or abuse of analgesics and therapeutic doses of non-steroidal anti-inflammatory drugs have been implicated in renal papillary necrosis (RPN). Several drugs implicated in RPN undergo metabolic activation, via prostaglandin synthetase (PGS) and / or lipoxygenase (LO) systems in papilla, forming potentially damaging free radicals, providing an attractive theory to account for the necrosis. This thesis demonstrated interspecies and intrarenal variation in terms of renal PGS and LO activities. PGS was primarily responsible for arachidonic acid (AA)-dependent metabolism of xenobiotics in rabbit, while in a combination of PGS and LO catalysed drug cooxidation in rat kidney. In contrast in man, AA-dependent cooxidation of drugs in renal tissue occurred via the 5-lipoxygenase, which was predominately located in the papilla. These results indicated that the commonly used laboratory animals, rabbit and rat, are not suitable models for studying RPN in man. These studies also offer a potential explanation for a long-standing anomaly. PGS was thought to be central to the development of RPN but it has been difficult to equate the involvement of PGS with the fact that many papillotoxic compounds are also PGS inhibitors (eg, indomethacin, mefenamic acid). However, this study suggests that 5-LO may be responsible for RPN, either by metabolic activation of drugs or production of pro-inflammatory 5-LO products, altering the renal eicosanoid balance and subsequently renal haemodynamics, thereby precipitating necrosis. This hypothesis was further strengthened by the increased activity of renal 5-LO noted in animal models of both diabetic- and chemically-induced papillotoxicity. Unfortunately, administration of 5-LO inhibitors did not protect against this chemically-induced papillotoxicity. It is possible that inhibitors of 5-LO may provide protection against, or reverse, drug- or disease-induced nephropathy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available