Function and regulation of P-glycoprotein in the liver of teleost fish

P-glycoptotein (P-gp), an active transmembrane exporter, transports various substances across cell membranes, sharing a similar set of substrates with other transporters in a coordinated system that maintains cellular chemical homeostasis. Increased expression of these transporters in aquatic animals results in the multi-xenobiotic resistance (MXR) phenotype, increasing survival and reproduction in contaminated environments. Known as chemosensitizers, inhibitors of these proteins enable toxic substrates to accumulate in tissues, heightening sensitivity and causing adverse effects at lower external concentrations. While extensively studied in mammals, the physiological functions and environmental relevance of fish P-gp are still emerging fields. To gain insight into the function and regulation of P-gp in fish, a series of studies was conducted examining the interaction of P-gp with its substrates and inhibitors at the biochemical, cellular, tissue, and whole animal levels in rainbow trout (Oncorhynchus mykiss). In cultured trout hepatocytes, experiments showed that four well-known mammalian chemosensitizers (cyclosporin A [CsA], quinidine, valspodar, and verapamil) competitively inhibited rainbow trout P-gp transport of rhodamine 123 (R123) and cortisol, at similar concentrations as reported for mammalian P-gp. Accumulation and efflux assays in trout hepatocytes showed that trout P-gp has similar binding sites and affinities for the known mammalian P-gp substrates doxorubicin, R123, and vinorelbine, while trout P-gp has a higher affinity for cortisol. P-gp inhibition by CsA caused small but significant changes in ivermectin distribution in trout blood and brain, suggesting that P-gp plays a smaller role in xenobiotic protection in fish than it does in mammals. Fish P-gp functions very similarly to mammalian P-gp, but with lineage-specific adaptations due to different chemical exposures and divergent evolutionary histories.