LITMIR.BIZ

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Jessica Enogieru^1,3, Dina Buitrago¹, and Kathleen M. Giacomini¹

       1 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA

       2 Drug Metabolism, Gilead Sciences Inc., Foster City, CA, USA

       3 Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, CA, USA

2.1 OVERALL INTRODUCTORY SECTION

      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.

CATION TRANSPORTERS: OCT1, OCT2, OCT3 (OTHER SECTION: SLC19A2, SLC19A3, PMAT)

      2.2 INTRODUCTION TO THE OCT FAMILY

      Within the human SLC22 transporter family, the electrogenic OCT subfamily consists of three members: OCT1 (SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). These transporters play important physiological and pharmacological roles, as they transport a variety of structurally diverse endogenous compounds and xenobiotics that have a net positive charge at physiological pHs. Alterations in the expression and function of these transporters can lead to various pathophysiological conditions. As the first member of the family, rat OCT1 (Slc22a1) was cloned and characterized in 1994, followed by rat OCT2 (Slc22a2) in 1996 [1]. The third member, OCT3, was identified and cloned in both rat and human in 1998 [1]. These three transporters share similar transport mechanisms and have overlapping ligand specificities; however, they differ in terms of their tissue distribution and the mechanisms involved in the regulation of their expression.

      2.2.1 Tissue Distribution

Despite the similarity of ligand specificity and transport function, the tissue distribution of the three OCTs varies greatly in humans and other species (Fig. 2.1, Table 2.1). Though expressed in many tissues, human OCT1 is most highly expressed in the liver and localized to the basolateral membrane of hepatocytes [1]. In rodents, high expression of OCT1 is also observed on the sinusoidal membrane of hepatocytes [1]. However, the expression and location of OCT1 in the kidney differs between human and rodents. Whereas in rodents, OCT1 is also expressed in the kidney and located on the basolateral membrane of proximal tubules, very low levels of OCT1 mRNA are detected in human kidney [6]. In addition to the expression pattern in the kidney and liver of rodents, Oct1 is also expressed in rodent intestine, and on the basolateral membrane of enterocytes. In contrast, in the trachea and bronchi of human, rat, and mouse, OCT1 appears to be expressed on the luminal membrane of epithelial cells [1]. In addition, low expression levels of hOCT1 have been detected in other tissues including brain, heart, skeletal muscle, peripheral leukocytes, adrenal gland, mammary gland, immune cells, and adipose tissue [7].

FIGURE 2.1 Tissue distribution and membrane localization of organic cation and zwitterion transporters. Created with BioRender.com.

      In comparison to OCT1, OCT2 has a more restricted expression pattern. It is most highly expressed in the kidney and is generally considered to be a “kidney‐specific” uptake OCT. In human kidney, OCT2 is expressed in all three segments of the proximal tubules [6], whereas in rat kidney Oct2 is located primarily to the S2 and S3 segments [1]. OCT2 is localized to the basolateral membrane of renal and intestinal epithelial cells [2]. In the lung, OCT2, like OCT1, is expressed at low levels on the luminal membrane of airway epithelia [1]. In brain, OCT2 (and OCT1) is expressed on the apical side of brain microvessel endothelial cells from humans, rats, and mice [8]. Low levels of expression of OCT2 have also been reported in brain parenchyma, thymus, placenta, and the inner ear [7].

In contrast to OCT1‐2, OCT3 has a wider tissue distribution with relatively high expression levels in skeletal muscle, placenta, salivary glands, heart, brain, adrenal gland, trachea, small intestine, and uterus [7]. The human OCT3 is also expressed in tumors and cancer cell lines [1]. In rodents, expression of Oct3 has been detected in additional organs, as well as Sertoli cells and basophile granulocytes [1]. The subcellular localization of OCT3 is tissue‐specific. OCT3 is localized to the basolateral membrane of the trophoblast in placenta and to the sinusoidal membrane of hepatocytes; whereas in the lung and intestine, it is localized to the apical membrane of epithelial cells [1, 7]. OCT3 has been observed in multiple brain regions in rodents, including the hippocampus, area postrema, subfornical organ, medial hypothalamus, and ependym of the third ventricle [1] and may serve as a low‐affinity reuptake transporter for neurotransmitters. In salivary glands, the OCT3 protein is localized to both basolateral and apical membranes of the secretory epithelial cells [9].

TABLE 2.1 Tissue distribution of organic cation and zwitterion transporters in humans [1–5]

Gene	Protein	Human tissue distribution
SLC22A1	OCT1	Liver, stomach, intestine, colon, spleen, trachea, lung, urinary bladder, skeletal muscle, heart, brain, mammary gland, leukocytes, Скачать книгу В начало < 14 15 16 17 18 19 20 21 22 23 > В конец