Peptide transporters in teleost fish: a look into the distant past for a more sustainable future

Abstract

The proton-coupled oligopeptide transporters, namely PepT1 (human gene, SLC15A1) and PepT2 (SLC15A2), have been subject to intense scrutiny due to their implications in absorption, reabsorption and distribution of peptidomimetic drugs, notably β-lactam antibiotics (Minhas & Newstead, 2020). While much is known about the pharmacology, molecular mechanisms and structure of the human orthologues (see for example Killer et al., 2021; Sala-Rabanal et al., 2008), less attention has been paid to lower vertebrates, in particular fish. In this issue ofThe Journal of Physiology, Vacca et al. (2022) help to bridge this knowledge gap by using a combination of phylogenetic, biochemical and biophysical approaches to characterize two distinct genes of the Atlantic salmon (Salmo salar) PepT2. Data are put forward that these transporters are expressed, thus potentially serving a physiological purpose, in fish epithelial and neural tissues. The exquisitely conserved mechanistic properties of teleost peptide transport unveiled here showcase the essential role of this ancient family of genes in weathering the selective pressures of protein homeostasis. Critically, this work puts the spotlight on how by-products of human activity may be adding to the ongoing environmental emergency: β-lactams, such as penicillin derivatives and cephalosporins, which are among the most heavily used antibiotics in global healthcare and industrial land farming, are increasingly polluting streams, lakes and oceans, from where they may find their way into the fish bloodstream through gill, intestine or kidney PepTs. Vacca et al. (2022) focus primarily on cultured salmon, and periodic food safety screenings, such as those performed by the Norwegian Institute of Marine Research, ensure that levels of contaminants in farmed seafood are negligible (see, for example, https://www.hi.no/en/hi/nettrapporter/ rapport-fra-havforskningen-en-2021-40); however, less is known about wild-caught fish and shellfish, which are a major part of the diet in many parts of the world. Pharmacokinetics data seem to suggest β-lactam antibiotics do not significantly accumulate in seafood of human consumption, such as the gilthead sea bream (Sparus aurata) (Katharios et al., 2004), thereby questioning the likelihood that they may end up on our dinner plate. But these studies are still few and far between, and more research is needed to determine the movement of pollutants along the food chain. Most importantly, the biological, physiological and ecological effects of sustained exposure of fish to runoff antibiotics, as well as how this is contributing to the worldwide antibiotic resistance crisis, remain to be systematically investigated. As industrialization presses on, work in the field of fish transport physiology as that presented here by Vacca et al. (2022) is crucial, not merely for a deeper understanding of the cellular and pharmacological mechanisms involved, but perhaps to ignite a tidal change regarding sustainable manufacturing, use and disposal of pharmaceuticals.