Читать книгу Drug Transporters - Группа авторов - Страница 29

Transporters in the solute carrier superfamily (SLC) play critical roles in the absorption and disposition of numerous solutes in the human metabolome. Though many transporters such as the neurotransmitter transporters in the SLC6 family are highly selective for one particular substrate, other transporters are more promiscuous, playing a role in the disposition of many molecules. These more promiscuous transporters are nevertheless constrained by particular physicochemical properties of their ligands. The focus of this chapter is on the transporters for two major categories of solutes: organic cations and zwitterions. The focus, in general, will be on the more promiscuous transporters for these solutes, rather on transporters with a high degree of specificity. The chapter begins with a discussion of organic cation transporters (OCTs). Here, there is a major focus on the three OCTs in the SLC22 family, OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). In addition, thiamine transporters (THTR‐1 (SLC19A2) and THTR‐2 (SLC19A3)) are included, as these have been shown to interact with many prescription drugs. PMAT1 (SLC29A4), a transporter in the equilibrative nucleoside transporter family (SLC29, ENT), is also included, as it has been shown to be selective for a diverse array of organic cations.

Zwitterion transporters are described in the second section of the chapter. The focus here is exclusively on the zwitterion transporters in the SLC22 family, which includes OCTN1 (SLC22A4), OCTN2 (SLC22A5), SLC22A15 (SLC22A15), and CT2 (SLC22A16). In addition, a short section on Octn3 (Slc22a21) is included; though not described in humans, the transporter plays an important role in the disposition of carnitine and its analogs in other animals.

For both the organic cation and zwitterion transporters, information is provided on their tissue distribution, ligand selectivity, and transport mechanism, which for many of the transporters may be ligand specific. In addition, we include information from genetically engineered mouse models, as well as human genetic and pharmacogenomic studies describing clinical associations between genetic polymorphisms or mutations in the individual transporters and clinical phenotypes. As over half of the prescription drugs are basic compounds, polymorphisms in OCTs have been associated with many pharmacogenomic traits. Further, as carnitine, a zwitterion, is a key molecule in fatty acid oxidation, many associations with zwitterion transporters include phenotypes that are ultimately related to disorders in energy production. The chapter ends with a brief discussion of future research that is needed to advance our understanding of organic cation and zwitterion transporters.