◆ Research findings by Professor Ken Ihara and colleagues Faculty of Agriculture in the School of Natural Sciences have been published in the journal *Environmental Science & Technology*
Release Date:
The effects of GPCR inhibitors prescribed to humans on fish via wastewater
自然科学系農学部門の井原賢教授を責任著者とする研究グループ（高知大学、京都大学、大連工科大学、Centre for Ecology and Hydrology、UK）の研究成果が「Environmental Science & Technology」誌に2024年12月26日付で掲載されました。
It has become clear worldwide that pharmaceuticals ingested by humans flow into wastewater treatment plants along with feces and urine, and are released into water systems such as rivers after undergoing wastewater treatment.Half of all prescription drugs are designed to inhibit G protein-coupled receptors (GPCRs). Representative GPCR inhibitors include antihypertensive drugs, antiallergic drugs, vasodilators, and antipsychotics. Because these drugs act on nerve cells, there are concerns about abnormalities in the reproduction and behavior of aquatic organisms, environmental responses, and the destruction of aquatic ecosystems.Professor Ken Ihara has been conducting research to clarify the impact on ecosystems of pharmaceuticals that act on nerve cells and are discharged into the aquatic environment via sewage. He was the first in the world to demonstrate that the active ingredients of these pharmaceuticals can be detected in sewage and river water. He also made the world’s first discovery that antidepressants inhibit not only human monoamine transporters but also receptors in fish (zebrafish).
In this study, using cellular assays capable of quantifying the pharmacological activity of GPCR inhibitors, we demonstrated for the first time worldwide that these inhibitors block histamine, adrenergic, and dopamine receptors not only in humans but also in fish (zebrafish). Furthermore, we showed that the potency of pharmacological activity differs between human and zebrafish GPCRs even for the same drug.We used molecular docking simulations (*1) to demonstrate that these species-specific differences in pharmacological activity are attributable to differences in the amino acid sequences of the GPCRs.
We also measured the pharmacological activity of 30 types of GPCR inhibitors and successfully ranked them by potency. Furthermore, we examined antidepressants that are widely used in both Japan and the United Kingdom and compiled a list of GPCR inhibitors that warrant particular attention for research, based on their pharmacological potency, high concentrations in wastewater effluent, and the need to protect aquatic ecosystems.As a result, we demonstrated that the impact of pharmaceuticals polluting the environment on fish should be assessed based on their pharmacological activity against zebrafish GPCRs rather than human GPCRs. We also conducted surveys of wastewater treatment plants in Japan and the UK, revealing differences in the actual presence of antidepressants in wastewater between the two countries.
From the perspective of protecting aquatic ecosystems, these research findings will lead to further investigations into the actual conditions and the conduct of in vivo (Note 2) toxicity tests.
Paper Title: Using Zebrafish G Protein-Coupled Receptors to Gain a Better Understanding of the Impact of Pharmaceuticals in Wastewater on Fish
Authors: Han Zhang, Mingyuan Cao, Mariko O. Ihara, Monika D. Jürgens, Andrew C. Johnson, Jingwen Chen, Hiroaki Tanaka, Masaru Ihara
Journal Title: Environmental Science & Technology (2024)
*1 Molecular docking simulation: A method for simulating interactions between molecules such as drugs and proteins
*2 in vivo: A test in which human or animal tissue is used in test tubes, culture dishes, or similar containers to artificially recreate an environment similar to that inside the body, in order to detect the drug’s response.