Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) derivative of phenylacetic acid, which elicits its therapeutic effects via inhibition of cyclooxygenase (Ortiz, 2017; Patrignani & Patrono, 2015). Diclofenac is globally used by millions of people mainly for the treatment of pain, inflammation, degenerative joint disease, rheumatoid arthritis, dysmenorrhoea and trauma (Ahmed et al., 2019; Aygun, Kaplan, Odaci, Onger, & Altunkaynak, 2012). Indeed, global diclofenac consumed yearly has been estimated to be approximately 940 tons (Zhang, Geissen, & Gal, 2008). Although diclofenac is an effective chemotherapeutic drug, its harmful effects in both animals and humans are associated with inhibition of prostaglandin biosynthesis. Specifically, diclofenac-mediated nephropathy, hepatotoxicity and ulceration, which are well-documented, have been related to the induction of oxidative damage (Ahmed, Gad, & El-Raouf, 2017;

The present study investigated the impact of coexposure to fluoride and diethylnitrosamine (DEN) on hepatorenal function in adult rats. The animals were exposed to fluoride (15 mg/L in drinking water) and DEN (10 mg/kg) singly or coexposed to both compounds for 14 days. Results demonstrated that the fluoride or DEN mediated increase in hepatorenal toxicity was intensified in the coexposure group. Additionally, the decrease in antioxidant enzyme activities as well as the elevation in reactive oxygen and nitrogen species, and lipid peroxidation was markedly aggravated in rats coexposed to DEN and fluoride. Furthermore, the increase in levels of nitric oxide, tumor necrosis factor-α and interleukin-1β, myeloperoxidase and caspase-3 activities as well as histological lesions was more pronounced in the liver and kidney of rats coexposed to DEN and fluoride. Conclusively, coexposure to fluoride and DEN exacerbated hepatorenal damage via enhancement of oxido-inflammatory responses and caspase-3 activation in rats. K E Y W O R D S caspase-3, coexposure, diethylnitrosamine, fluoride, oxido-inflammation, rats J Biochem Mol Toxicol. 2019;33:e22327.wileyonlinelibrary.com/journal/jbt