GDC-0152 synthesis Although enantioselective accumulation of
Although enantioselective accumulation of metalaxyl in organisms is an integrated outcome of bio-process including absorption, transportation, and transformation, it is observed in our study that catalysis of CYP450 may lead to the enantioselective accumulation of metalaxyl. However, the mechanisms on enantioselective accumulation of metalaxyl involving CYP450 are still far away from full disclosure. Enantioselective interaction with CYP450 has been reported for some pollutants in organisms (Kania-Korwel et al., 2008, Lu et al., 2011). Kania-Korwel et al. (2008) revealed that (+)-PCB 136 had stronger ability to bind to CYP450 enzymes such as CYP2B and CYP3A compared to (-)-PCB 136. (S)-naringenin was 2-fold more potent to inhibit CYP19 and CYP2C19 than (R)-naringenin, while (R)-naringenin was 2-fold more inhibitory potent for CYP2C9 and CYP3A (Lu et al., 2011). Accordingly, the enantioselective attenuation of metalaxyl observed in the present study is probably related to the enantioselective interaction of metalaxyl with CYP450. But the hypothesis has to be proven by further study.
Acknowledgements The work was financially supported by the National Nature Science Foundation of China (21677126, 21320102007) and Research Center for Air Pollution and Health, Zhejiang University.
Introduction Corticosteroids are a class of chemicals that includes natural steroid hormones (glucocorticoids and mineralocorticoids), produced from cholesterol in the adrenal GDC-0152 synthesis of vertebrates, and their synthetic analogues. Fish interrenal glands are capable of secreting adrenocortical steroids. Cortisol has been found in the blood and tissues of several fish species, including rainbow trout (Oncorhynchus mykiss), brown trout (Salmo trutta) (Sloman et al., 2001), and Mozambique tilapia (Oreochromis mossambicus); (Johnstone et al., 2013). Fish kidneys and associated adrenal glands are structured differently than other vertebrates (Perry and Capaldo, 2011). Natural corticosteroids are involved in a broad range of physiological processes (e.g., inflammation) by reducing the response to stress as well as glucose, lipid and protein metabolism. Synthetic equivalents of corticosteroids act in similar ways and can have higher corticosteroid potencird than natural variants (Bentz, 2014). 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 cortisol 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.