Dexamethasone DEX a potent synthetic glucocorticoid drug
Dexamethasone (DEX), a potent synthetic glucocorticoid drug, is effective for treatment of a range of inflammatory and autoimmune conditions as well as the reduction of side effects associated with chemotherapy. On the Czech Republic pharmaceutical market, DEX is incorporated into eighteen drugs used for treatment of systemic hormonal and sensory organ problems. The Czech Republic was the eighteenth largest EU pharmaceutical market in 2012 (EFPIA, 2013), and its DEX use was 46.13kg in 2013 (SUKL, 2015). In the last few decades, a vast range of synthetic steroid drugs has been produced and released into the aquatic environment where, as a group, they are potential contaminants that disrupt non-target organisms in aquatic environments (Kumar et al., 2015). The concentration of DEX was reportedly 38ngL−1 downstream from a swine farm (Liu et al., 2012). It was reportedly between 1.2 and 23ngL−1 in wastewater influent (Chang et al., 2007, Liu et al., 2011). In river water downstream from a pharmaceutical manufacturing plant discharge, it was 23μgL−1 (Creusot et al., 2014). Because of growing concerns about the potential adverse impacts of pharmaceuticals on non-target aquatic organisms, DEX was prioritized by ranking schemes for environmental risk assessment (Roos et al., 2012); it is prescribed for its potent glucocorticoid effect. Several recent studies investigated the effects of glucocorticoids at environmentally relevant levels on fish secondary sexual characteristics (Kugathas and Sumpter, 2011, Kugathas et al., 2012, Kugathas et al., 2013). Dexamethasone was found to affect reproduction, growth and development in fathead minnows after chronic exposure at 500μgL−1 (LaLone et al., 2012). It also significantly reduced resting plasma Misoprostol australia levels and induced interrenal cell atrophy following treatment with 50mgg−1 DEX for 7d in Chinook salmon (McQuillan et al., 2011) and was found to potentially cause oxidative stress in liver tissue at 0.3 and 3.0μgkg−1 doses, disturbing the antioxidant system in the gonads of male Hoplias malabaricus after trophic DEX exposure at 0.03–3.0μgkg−1 doses (Guiloski et al., 2015). Currently, there is limited information about its toxicity in the aquatic environment and the eventual effects on physiological processes in fish. The hepatic cytochrome P450 (CYP450) superfamily is essential for metabolising foreign chemicals, fatty acids, vitamins, hormones and other compounds and consists of 18 subfamilies (Uno et al., 2012). The number of discovered CYP genes is increasing as a result of intense work with CYP450 gene structures (Kubota et al., 2013). The first three subfamilies (CYP1, CYP2 and CYP3) are mainly responsible for metabolising xenobiotics, and variations in their expression and activity can be used as indicators of exposure to environmental contaminants. CYP1A is a catalyst of environmental pollutants, including human pharmaceuticals (Laville et al., 2004, Navas et al., 2004, Smith et al., 2012); therefore it is critical in finding the pathways leading to detoxification. This enzyme is highly conservative among vertebrates. Mammals, birds and some fish species (eel and rainbow trout) possess genes for two CYP1A isoforms (Berndtson and Chen, 1994, Rifkind et al., 1994, Gorman et al., 1998, Mahata et al., 2003). A widely used assay for CYP1A is the measurement of EROD activity, which is routinely used as a biomarker to determine the presence of organic pollutants (Mandal, 2005). The majority of CYP450s are substrate-inducible via mechanisms often including ligand activation of transcription factors such as the aryl hydrocarbon receptor (AhR), pregnane X receptor, constitutive androstane receptor and others. The mechanism of CYP1A induction in fish is well known; numerous bioactive compounds induce CYP1A via binding to AhR and subsequent initiation of transcription. The less-studied mechanism of CYP450 regulation involves stabilization of mRNA and changes in protein turnover, leading to an increase in CYP450 activity, which largely depends on biotransformation of environmental pollutants in aquatic organisms. Factors that alter this activity might also alter the toxicity of CYP450 substrates.