OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies

Abstract

The human organic anion and cation transporters are classified within two SLC superfamilies. Superfamily SLCO (formerly SLC21A) consists of organic anion transporting polypeptides (OATPs), while the organic anion transporters (OATs) and the organic cation transporters (OCTs) are classified in the SLC22A superfamily. Individual members of each superfamily are expressed in essentially every epithelium throughout the body, where they play a significant role in drug absorption, distribution and elimination. Substrates of OATPs are mainly large hydrophobic organic anions, while OATs transport smaller and more hydrophilic organic anions and OCTs transport organic cations. In addition to endogenous substrates, such as steroids, hormones and neurotransmitters, numerous drugs and other xenobiotics are transported by these proteins, including statins, antivirals, antibiotics and anticancer drugs. Expression of OATPs, OATs and OCTs can be regulated at the protein or transcriptional level and appears to vary within each family by both protein and tissue type. All three superfamilies consist of 12 transmembrane domain proteins that have intracellular termini. Although no crystal structures have yet been determined, combinations of homology modelling and mutation experiments have been used to explore the mechanism of substrate recognition and transport. Several polymorphisms identified in members of these superfamilies have been shown to affect pharmacokinetics of their drug substrates, confirming the importance of these drug transporters for efficient pharmacological therapy. This review, unlike other reviews that focus on a single transporter family, briefly summarizes the current knowledge of all the functionally characterized human organic anion and cation drug uptake transporters of the SLCO and the SLC22A superfamilies.

Figure 1

Expression of OATPs in selected human epithelial cells. For more details, see the text. OATP1A2 expression in cholangiocytes has been demonstrated, but it has not yet been localized to a distinct cell membrane. (A) apical; (B) basolateral.

Figure 2

Homology models of members of the SLCO (OATP1B1) and the SCL22A (OAT1) families. The models were generated using Phyre² (Kelley and Sternberg, 2009) and are based on the E. coli glycerol-3-phosphate transporter. (A) OATP1B1 is shown viewed from the extracellular side (left) and from within the lipid bilayer (right). For clarity, transmembrane domains 2 and 4 are omitted in the right panel. Amino acids mentioned in the text are indicated. (B) OAT1 is shown viewed from the extracellular side (left) and from within the lipid bilayer (right). For clarity, transmembrane domains 2 and 4 are omitted in the right panel. The indicated amino acids were identified as important for the function of OAT1 and face the putative aqueous pore (Hong et al., 2004; Perry et al., 2006; Rizwan et al., 2007).

Figure 3

Expression of OATs in different human epithelia. For more details, see the text. OAT1 localization in the choroid plexus and OAT2 localization in the liver is inferred from rodent data. (A) apical; (B) basolateral.

Figure 4

Cartoon of tertiary active transport mechanism for OAT-mediated uptake of organic anions. The primary active Na⁺/K⁺-ATPase generates the sodium gradient that is used by the secondary active Na⁺-dicarboxylate cotransporter (NaDC3) to maintain a high intracellular concentration of α-ketoglutarate, which is used to drive uptake of other organic anions by OAT1 and OAT3.

Figure 5

Expression of OCTs in human epithelial cells. For more details, see the text. Localization of OCTN1 in the kidney is concluded based on rodent data. (A) apical; (B) basolateral.