Homeostatic regulation of copper in a marine fish simulated by a physiologically based pharmacokinetic model

Copper (Cu) is an essential yet potentially toxic metal, thus delicate homeostatic controls are developed in the fish. In this study, a physiologically based pharmacokinetic (PBPK) model was developed to simulate the homeostatic regulation of Cu in a marine fish (Terapon jarbua) under dietary and waterborne exposures. In this model, fish were schematized as a six-compartment model, with the intestine being divided into two sub-compartments (chyme and gut wall). The blood was assumed to be the "carrier" distributing Cu into different compartments. The transfer rates between different compartments were determined in fish during Cu exposure (20 d) and depuration (20 d). The differences in Cu transfer from chyme to gut wall between dietary and waterborne treatments suggested that the intestine regulated the dietary uptake and re-absorption of Cu from the chyme. The extremely low uptake rate constant (0.0013 d^-1) for gills under waterborne exposure indicated that gills strongly restricted Cu uptake from the ambient water. For both treatments, the liver had considerable input rate through the enterohepatic circulation and comparably high exchange rate with the blood, suggesting that the liver can efficiently accumulate newly absorbed Cu. The differences in Cu output from the liver between dietary and waterborne treatments suggested that it can effectively regulate the redistribution of Cu. All of these observations demonstrated that the liver played the central role in Cu homeostasis by serving as the main depository and distributing center. Modeling results also indicated that renal and branchial excretion was of minor importance, whereas biliary excretion combined with defecation played the most important role in whole-body Cu elimination in marine fish. The effective regulation by the "Blood-Liver-Intestine" cycle could be the main reason for the relatively low levels of Cu in fish.