title: Novel mechanisms of nonsteroidal anti-inflammatory drug-induced renal toxicity.
abstract: The exact mechanism(s) of NSAID-induced nephrotoxicity remains unclear, but most theories centre on the initial inhibition of COX and the subsequent perturbation of the numerous actions of COX in the kidney. Since the nineteenth century no NSAIDs have been developed that are devoid of renal adverse effects, including the COX-2 selective inhibitors. Formation of renal eicosanoids from arachidonic acid is significantly increased in the presence of various stimuli, and metabolic degradation of arachidonic acid and its biologically active metabolites is crucial to the maintenance of renal homeostatic mechanisms. An important family of enzymes that function in this capacity are the uridine 5'-diphosphate glucuronosyltransferases (UGTs) that variously metabolise arachidonic acid and its metabolites. This review focuses on arachidonic acid and its biologically active metabolites and their respective fates subsequent to COX inhibition by NSAIDs. The common involvement of UGT in the metabolism of arachidonic acid, eicosanoids and NSAIDs is discussed in the context of novel mechanisms of NSAID-induced nephrotoxicity.
authors.affiliation: Flinders University and Flinders Medical Centre, Department of Clinical Pharmacology, Bedford Park, Adelaide 5042, Australia. Kathie.knights@flinders.edu.au
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Knights
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Tsoutsikos
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases