Interactions of Environmental Chemicals and Natural Products With ABC and SLC Transporters in the Digestive System of Aquatic Organisms

Abstract

An organism’s diet is a major route of exposure to both beneficial nutrients and toxic environmental chemicals and natural products. The uptake of dietary xenobiotics in the intestine is prevented by transporters of the Solute Carrier (SLC) and ATP Binding Cassette (ABC) family. Several environmental chemicals and natural toxins have been identified to induce expression of these defense transporters in fish and aquatic invertebrates, indicating that they are substrates and can be eliminated. However, certain environmental chemicals, termed Transporter-Interfering Chemicals or TICs, have recently been shown to bind to and inhibit fish and mammalian P-glycoprotein (ABCB1), thereby sensitizing cells to toxic chemical accumulation. If and to what extent other xenobiotic defense or nutrient uptake transporters can also be inhibited by dietary TICs is still unknown. To date, most chemical-transporter interaction studies in aquatic organisms have focused on ABC-type transporters, while molecular interactions of xenobiotics with SLC-type transporters are poorly understood. In this perspective, we summarize current advances in the identification, localization, and functional analysis of protective MXR transporters and nutrient uptake systems in the digestive system of fish and aquatic invertebrates. We collate the existing literature data on chemically induced transporter gene expression and summarize the molecular interactions of xenobiotics with these transport systems. Our review emphasizes the need for standardized assays in a broader panel of commercially important fish and seafood species to better evaluate the effects of TIC and other xenobiotic interactions with physiological substrates and MXR transporters across the aquatic ecosystem and predict possible transfer to humans through consumption.

A Review of P-Glycoprotein Function and Regulation in Fish

“…In fish, as well as in mammals and invertebrates, P-gp can play a role in preventing the absorption of chemicals from the intestinal tract, protecting the organism from potentially harmful substances [53]. P-gp is expressed in the apical membrane of enterocytes, where it actively pumps substrates back into the intestinal lumen, limiting their uptake into the bloodstream [11].…”

“…Playing a key role in this chemical defense system in fish is P-gp, which operates in tandem with other defense components. Fish tissues commonly express P-gp alongside other transporters and enzymes, including phase I functionalization enzymes (e.g., cytochrome 450 oxidases), phase II conjugating enzymes (e.g., glutathione S-transferase, sulfotransferase, UDP-glucuronosyltransferase) [75,[92][93][94][95], phase III exporters (e.g., multidrug resistance proteins [MRPs], breast cancer resistance protein [BCRP]) [41,75,93,96]), and solute carrier (SLC) transporters (e.g., organic anion transporting polypeptides [OATPs], organic anion transporters [OATs], organic cation transporters [OCTs], and multidrug and toxin extrusion proteins [MATEs]) [53,97,98]. Although the ABCB (MDR, P-gp) and ABCC (MRP) families of transporters are both referred to as "multidrug resistance proteins", they are distinct classes of transporters that perform different functions in the chemical defense system.…”

“…Importer proteins tend to be expressed in the same cells as exporters, usually on the opposite sides of barrier tissues. The SLC21 (OATP) and SLC22 (OAT, OCT) families of secondary active transporters in particular are commonly expressed with P-gp in fish tissues [53,97,98]. These transport proteins import both membrane-permeable (lipophilic) and non-membrane permeable (hydrophilic) molecules.…”

TICBase: Integrated Resource for Data on Drug and Environmental Chemical Interactions with Mammalian Drug Transporters

“…In aquatic organisms, drug transporter inhibition and the resulting chemosensitization of cells and organisms toward toxic environmental chemical bioaccumulation was first described over 30 years ago and has since been confirmed in non-aquatic organisms. [15][16][17] Recent research has shown that environmental chemicals similarly bind and inhibit vertebrate drug transporter function for mouse ABCB1 and tuna ABCB1. 18,19 These so-called transporterinterfering chemicals (or TICs) are typically present at low levels in food, but the sum of individual compounds can reach levels high enough to inhibit drug transporters and trigger consumption advisories based on the risk of developing cancer.…”

“…Similar challenges exist regarding environmental chemicals. In aquatic organisms, drug transporter inhibition and the resulting chemosensitization of cells and organisms toward toxic environmental chemical bioaccumulation was first described over 30 years ago and has since been confirmed in non‐aquatic organisms 15–17 . Recent research has shown that environmental chemicals similarly bind and inhibit vertebrate drug transporter function for mouse ABCB1 and tuna ABCB1 18,19 .…”