The ATP-binding cassette (ABC) transporter gene superfamily encodes membrane proteins that transport their substrates in an energy-dependent manner against concentration gradients. Genes are classified as ABC transporter family members based on the sequence identity of their ATP-binding domains, also referred to as nucleotide binding domains (NBDs), which are highly conserved among species (Annilo et al., 2006). Humans have 48 ABC transporter genes, organized into 7 subfamilies (ABCA to G). The 7 subfamilies are represented in all eukaryotic genomes, indicating an ancient origin (Dean and Annilo, 2005). Many human ABC genes have functionally conserved orthologs in animal models, permitting the study of these transporters in vivo.

Zebrafish (Danio rerio) have 52 ABC transporter genes, with orthologs for 77% of the 48 human ABC transporters (Annilo et al., 2006). The teleost fish lineage, to which zebrafish belong, underwent an ancient whole-genome duplication event. The ABC transporters that are the most ubiquitously expressed, such as the ABCB half-transporters (HTs), the ABCE and ABCF families, and the ABCC family, have the fewest number of duplications. The ABCA, ABCB full-transporters (FTs), and ABCG2 families underwent the most duplications (Annilo et al., 2006).

This review will focus on the current body of literature on zebrafish orthologs of mammalian multidrug resistance (MDR) transporters, also known as multixenobiotic resistance (MXR) ABC transporters, namely ABCB1 (which encodes ABCB1/ P-glycoprotein (P-gp)/ multidrug resistance protein 1 (MDR1)), ABCG2 (which encodes ABCG2/ breast cancer resistance protein (BCRP)) and ABCC1 (which encodes ABCC1/ multidrug resistance-associated protein 1 (MRP1)). For information regarding a wider analysis of ABC transporters across fish species, we refer the reader to comprehensive reviews by Ferreira, Luckenbach, and colleagues (Ferreira et al., 2014, Luckenbach et al., 2014). The MDR-associated ABC transporters have wide substrate specificities, which enables them to confer resistance to a plethora of drugs (Robey et al., 2018). MDR transporters are primarily expressed in the liver, kidneys, and intestines where they excrete substrates into the waste, and at protective barriers such as the blood-brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), placenta, ovaries, and blood-testes barrier (Brayboy et al., 2017; Kannan et al., 2009).

Characterization of the similarities and differences between zebrafish and human transporters is required to permit translational studies of transporter activity and drug bioavailability in zebrafish. Zebrafish have advantages over mammalian animal models, given their high fecundity, relatively low cost, and amenability to high-throughput screening (HTS), imaging and genetic manipulation. In addition to biomedical research, the study of zebrafish ABC transporters is pertinent to evaluating environmental pollution and toxicology, as ABC transporters are a major defense mechanism against toxic xenobiotics in aquatic species (Bard, 2000, Kurelec, 1992).