Drug Transporters - Группа авторов

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the disorder progresses, and patients experience a premature death. High doses of another B vitamin, biotin, eliminate these abnormalities, which do not recur if treatment is continued. Although THTR‐2 is a thiamine transporter that does not transport biotin [70], the disorder does not respond to thiamine [71]. Notably, biotin deficiency is associated with reduced expression of SLC19A3 in human leukocytes [72].

      Thiamine deficiency in the setting of alcoholism is associated with Wernicke’s syndrome, which acutely includes mental confusion, ataxia, and ophthalmoplegia and later progresses to memory loss and confabulation. A Wernicke’s‐like genetic syndrome has also been associated with SLC19A3 mutations (OMIM #606152) [67]. The disorder manifests clinically in adolescence with diplopia and nystagmus progressing to seizures [73]. Affected patients are not clinically thiamine deficient but respond to high doses of thiamine.

      Thus far, mutations in SLC29A4 have not been linked to a Mendelian autosomal recessive or dominant disease [67]. However, heterozygous loss‐of‐function mutations in SLC29A4 have been linked to autism spectrum disorders [74] and abnormalities in levels of serotonin and its metabolic end products. A common SLC29A4 intronic variant (rs3889348), which is associated with reduced expression of PMAT, has been linked to increased risk of metformin gastrointestinal intolerance in candidate gene studies [75].

      2.7 INTRODUCTION TO THE ZWITTERION TRANSPORTERS

      Within the human SLC22 transporter family, the zwitterion transporter subfamily is composed of hOCTN1 (SLC22A4), hOCTN2 (SLC22A5), FLIPT1/SLC22A15 (SLC22A15), and CT2 (SLC22A16), among others. These transporters play important physiological and pharmacological roles, acting in the influx and efflux of essential endogenous compounds (e.g., carnitine and ergothioneine), drugs, and various xenobiotics. Alterations in the expression and function of these transporters can lead to various pathophysiological conditions.

      2.7.1 General Tissue Distribution

      Both members of the novel OCT (OCTN) family are highly expressed in the kidney and are more ubiquitously expressed at low levels across a variety of tissues [1] (Table 2.1). OCTN1 is expressed most highly in whole blood, particularly within erythrocytes. It has broad tissue distribution at low levels, notably in the brain, small intestine, lung, and reproductive organs. In mice, Octn1 has been localized to the apical membrane of the renal proximal tubule. Consistent with the role of a transporter for the antioxidant ergothioneine, OCTN1 is expressed in tissues exposed to high oxidative stress, notably the kidney, liver, bone marrow/erythrocytes, eye lens, and seminal fluid [2]. Unlike the majority of related zwitterion transporters, OCTN1 appears to play a minimal role in the transport of carnitine. In humans, OCTN2 is expressed ubiquitously at low levels in most tissues. Highest expression is observed in skeletal muscle, brain, kidney, intestine, cardiac tissue, and reproductive organs. Many of these tissues have high energy demands and rely heavily on fatty acid β‐oxidation for ATP production. OCTN2 expression in these tissues ensures carnitine stores are available to conjugate to intracellular long‐chain fatty acids for translocation into the mitochondrial matrix where β‐oxidation occurs. In the kidney, OCTN2 is localized to the apical membrane of the renal proximal tubule where it functions largely in the reabsorption of renally excreted carnitine from urine to maintain systemic levels.

      In humans, SLC22A15 is ubiquitously expressed throughout all tissues in the body, although highest expression has been observed in the brain and bone marrow. Other species exhibit similar expression patterns, including primates (baboon, rhesus macaque, old world monkey), cattle, pigs, sheep, mice, rats, chickens, some lizards, and zebrafish [5]. Human SLC22A15 is mainly involved in the transport of ergothioneine, like OCTN1, and supports transport of other zwitterions and cations. CT2 is another high‐affinity carnitine transporter, but in contrast to OCTN2 and SLC22A15, expression is limited to the Sertoli cells of the testis, the kidneys, and bone marrow [1]. These tissues have high energy requirements, especially the testis, where carnitine plays a crucial role in spermatogenesis. Similar CT2 expression patterns are also found in primates, mice, cattle, and chicken.

      2.7.2 General Structure Function

      SLC22A15 and CT2 are both found on the plasma membrane and exhibit bidirectional function similar to OCTN1 and OCTN2. The genes encoding these transporters are found on distinct chromosomes, with SLC22A15 at locus 1q13 and SLC22A16 at locus 6q21. SLC22A15 contains 11 exons while SLC22A16 has two isoforms, one with 8 exons and one with 10 exons [76, 77]. SLC22A15 contains 547 amino acids, while CT2 contains 577 amino acids. SLC22A15 and CT2 have mRNA and protein sequence identity of 47% and 31%, respectively. While still considered family members of the OCTN subclade, these two transporters appear to have evolutionally diverged from each other and from the other two OCTNs [78]. SLC22A15 and CT2 have 50–52% mRNA sequence identity and 32–33% protein sequence identity to OCTN1 and OCTN2. However, the predicted topology of SLC22A15 and CT2 remains similar to OCTN1 and OCTN2, with 12 predicted transmembrane domains and cytoplasmic N‐ and C‐termini [1].

      2.7.3 Transport Mechanism

      Similar to the OCTs, the zwitterion transporters are believed to function through the alternating‐access transport mechanism as detailed in Section 2.2.3. Multiple transport mechanisms have been observed for the OCTN transporters, depending on substrate. The zwitterion transporters can function as uniporters, like OCT1‐3, translocating single substrates, or as cotransporters, transporting multiple substrates in the same direction (symport) or opposite directions (antiport) (Fig. 2.2b) [17]. OCTN1 transports the zwitterion ergothioneine via a sodium‐dependent symport uptake mechanism, but can transport other zwitterions (e.g., gabapentin) independent of sodium. OCTN1 can also act as a pH‐dependent proton/cation antiporter (e.g., TEA), or a bidirectional organic cation uniporter (e.g., acetylcholine). OCTN2 acts as a secondary active sodium‐dependent cotransporter for carnitine, facilitating symport of sodium and carnitine at a 1:1 ratio [2]. OCTN2 transport of some cations, including TEA, is sodium‐independent, while other cations are transported via proton/cation antiport [2]. SLC22A15 transports zwitterions, notably ergothioneine, carnosine, and carnitine, and certain organic cations in a sodium‐dependent manner [79]. CT2 transport is very selective for L‐ and D‐carnitine, betaine, and TEA. Carnitine transport by CT2 is partially sodium‐dependent, with uptake reduced by 50% when sodium is replaced with lithium. Unlike SLC22A15, CT2 demonstrates pH‐dependent transport for carnitine.

      2.8.1 Substrate and Inhibitor Selectivity

      OCTN1 was first cloned in 1997 from fetal liver tissue and found to influx the prototypical cation, TEA, in a saturable, pH‐sensitive manner (K m = 436 μM) [80]. In contrast to OCTs, OCTNs have a preference for zwitterions,

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