Are Pharmaceuticals with Evolutionary Conserved Molecular Drug Targets More Potent to Cause Toxic Effects in Non-Target Organisms?

Abstract

The ubiquitous use of pharmaceuticals has resulted in a continuous discharge into wastewater and pharmaceuticals and their metabolites are found in the environment. Due to their design towards specific drug targets, pharmaceuticals may be therapeutically active already at low environmental concentrations. Several human drug targets are evolutionary conserved in aquatic organisms, raising concerns about effects of these pharmaceuticals in non-target organisms. In this study, we hypothesized that the toxicity of a pharmaceutical towards a non-target invertebrate depends on the presence of the human drug target orthologs in this species. This was tested by assessing toxicity of pharmaceuticals with (miconazole and promethazine) and without (levonorgestrel) identified drug target orthologs in the cladoceran Daphnia magna. The toxicity was evaluated using general toxicity endpoints at individual (immobility, reproduction and development), biochemical (RNA and DNA content) and molecular (gene expression) levels. The results provide evidence for higher toxicity of miconazole and promethazine, i.e. the drugs with identified drug target orthologs. At the individual level, miconazole had the lowest effect concentrations for immobility and reproduction (0.3 and 0.022 mg L−1, respectively) followed by promethazine (1.6 and 0.18 mg L−1, respectively). At the biochemical level, individual RNA content was affected by miconazole and promethazine already at 0.0023 and 0.059 mg L−1, respectively. At the molecular level, gene expression for cuticle protein was significantly suppressed by exposure to both miconazole and promethazine; moreover, daphnids exposed to miconazole had significantly lower vitellogenin expression. Levonorgestrel did not have any effects on any endpoints in the concentrations tested. These results highlight the importance of considering drug target conservation in environmental risk assessments of pharmaceuticals.

Redox proteomic analysis of mytilus edulis gills: effects of the pharmaceutical diclofenac on a non‐target organism

“…This means that they may retain potential for bioactivity, even after deposition in the environment. In addition, the conservation of biochemical targets between humans and animals on the one hand, and non‐target organisms on the other, is likely to lead to non‐target effects . There is now significant concern internationally about the potential environmental implications of pharmaceuticals developed for humans and agricultural animals on non‐target species .…”

“…In addition, the conservation of biochemical targets between humans and animals on the one hand, and non-target organisms on the other, is likely to lead to non-target effects. [2] There is now significant concern internationally about the potential environmental implications of pharmaceuticals developed for humans and agricultural animals on non-target species. [1] Filter-feeding aquatic organisms such as mussels are of special interest in this regard, since they filter estuarine water very efficiently and are known to be capable of bioconcentrating pharmaceuticals and other xenobiotics in their tissues.…”

Interclonal proteomic responses to predator exposure in Daphnia magna may depend on predator composition of habitats

“…Indeed, it was shown that pharmaceutical inhibition of calmodulin in D. magna led to a decrease in gene expression of a cuticle protein and vitellogenin (Furuhagen et al . ). Therefore, calmodulin may also be involved in signal pathways leading to altered abundances of cuticle proteins and vitellogenins found during predator exposure in our study.…”

“…To get further information on similar proteins, all significant protein sequences were blastp-searched against NCBI nr and swissprot databases using local standalone blast (Geer et al 2010).…”

Avaliação ecogenotoxicológica de corante natural extraído de micro-organismo

“…(BAE et al, 2006;FREEMAN, 2007;LIU et al, 2007;KANHERE et al, 2014;DARSANA et al, 2015). O critério para a determinação da toxicidade aguda é a completa imobilização destes organismos após 24-48 horas de exposição à substância química em estudo (OECD Guideline 202, 2004 Sob condições adversas, as fêmeas podem responder com a produção de ovos de resistência, alterações no tempo de maturação reprodutiva e no número e tamanho de descendentes (COORS et al, 2004;PESTANA et al, 2010;FURUHAGEN et al, 2014;STANLEY et al, 2016;TRAUDT et al, 2016;BARATA et al, 2016). Do ponto de vista ecológico, alterações na reprodução podem acarretar em uma redução na taxa intrínseca de crescimento populacional dos organismos, a qual compromete a manutenção da população e eleva os riscos de extinções das populações locais (PESTANA et al, 2010).…”