Emerging Roles of the Human Solute Carrier 22 Family

The human solute carrier 22 family (SLC22), also termed the organic ion transporter family, consists of 28 distinct multi -mem-brane spanning proteins, which phylogenetically cluster together according to their charge specificity for organic cations (OCTs), organic anions (OATs), and organic zwitterion/cations (OCTNs). Some SLC22 family members are well characterized in terms of their substrates, transport mechanisms, and expression patterns, as well as their roles in human physiology and pharmacology, whereas others remain orphans with no known ligands. Pharmaco-logically, SLC22 family members play major roles as determinants of the absorption and disposition of many prescription drugs, and several, including the renal transporters, OCT2, OAT1 and OAT3, are targets for many clinically important drug-drug interactions. In addition, mutations in some of these transporters [SLC22A5 (OCTN2) and SLC22A12 (URAT1)] lead to rare monogenic disor-ders. Genetic polymorphisms in SLC22 transporters have been associated with common human disease, drug response, and vari-ous phenotypic traits. Three members in this family were deor-phaned very recently: SLC22A14, SLC22A15, and SLC22A24, and found to transport specific compounds, such as riboflavin (SLC22A14), anti-oxidant zwitterions (SLC22A15) and steroid con-jugates (SLC22A24). Their physiologic and pharmacological roles need further investigation. This review aims to summarize the sub-strates, expression patterns and transporter mechanisms of indi-vidual SLC22 family members and their roles in human disease and drug disposition and response. Gaps in our understanding of SLC22 family members are described.SIGNIFICANCE STATEMENT In recent years, three members of the SLC22 family have been deorphaned and found to play important roles in the transport of diverse solutes. New research has furthered our understand-ing of the mechanisms, pharmacological roles, and clinical impact of SLC22 transporters. This minireview provides an overview of the physiologic and pharmacologic roles and impact of genetic variants in the SLC22 family on disease and drug response, and summarizes recent studies deorphaning SLC22 family members.

Automated summary

The SLC22 family consists of membrane proteins that play important roles in the transport of solutes. They are involved in the absorption and disposition of prescription drugs, and mutations in some members can lead to rare monogenic disorders. Genetic polymorphisms in SLC22 transporters are associated with common human diseases and drug response. Three new members have recently been identified and their physiological and pharmacological roles need further investigation.