Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction.
Diclofenac (DF), a non-steroidal anti-inflammatory drug (NSAID), is largely regarded as one of the most devastating environmental toxicant in recent times, after accidental exposure via their food-chain lead to massive mortalities in three vulture species on the Asian subcontinent. Although the use of diclofenac was recently banned on the Indian subcontinent, following the favourable safety profile of meloxicam, its mechanism of toxicity remains unknown. In an attempt to establish this mechanism, we test three hypotheses using models established from either the domestic chicken (Gallus domesticus) or the African White-backed vulture (Gyps africanus). We demonstrate that both DF and meloxicam are toxic to renal tubular epithelial (RTE) cells following 12 h of exposure, due to an increase in production of reactive oxygen species (ROS), which could be temporarily ameliorated by pre-incubation with uric acid (UA). When cultures were incubated with either drug for only 2 h, meloxicam showed no toxicity in contrast to diclofenac. In both cases no increase in ROS production was evident. In addition, diclofenac decreased the transport of uric acid, by interfering with the p-amino-hippuric acid (PAH) channel. We conclude that vulture susceptibility to diclofenac results from a combination of an increased ROS, interference with UA transport and the duration of exposure.
Naidoo
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Section of Pharmacology, Faculty of Veterinary Science, Onderstepoort, South Africa. vinny.naidoo@up.ac.za
Swan
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D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D004008:Diclofenac / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004781:Environmental Exposure; D004785:Environmental Pollutants / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D046093:Falconiformes / Q000378:metabolism*; D020387:Food Chain; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077239:Meloxicam; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012082:Renal Veins / Q000187:drug effects; D013843:Thiazines / Q000633:toxicity; D013844:Thiazoles / Q000633:toxicity; D013997:Time Factors; D014527:Uric Acid / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004785:Environmental Pollutants; D027362:Organic Anion Transport Protein 1; D017382:Reactive Oxygen Species; D013843:Thiazines; D013844:Thiazoles; D004008:Diclofenac; D014527:Uric Acid; D000077239:Meloxicam