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Drug Transporters. Группа авторов
Читать онлайн.Название Drug Transporters
Год выпуска 0
isbn 9781119739876
Автор произведения Группа авторов
Жанр Медицина
Издательство John Wiley & Sons Limited
Abbreviations:
MPP+ : N‐methyl‐4‐phenylpyridinium.
TEA: tetraethylammonium.
ASP+ : 4‐(4‐(diethylamino)styryl)‐N‐methylpyridinium.
NBD‐MTMA: N,N,N‐trimethyl‐2‐[methyl(7‐nitrobenzo[c][l,2,5]oxadiazol‐4‐yl)amino]ethanaminium.
2.3.4 Human Genetic Studies
Human OCT1 is the most polymorphic of the OCTs in terms of missense variants. In 2002, 7 missense variants and an amino acid deletion, 420del, in OCT1 were identified in samples from Europeans, and in 2003, 14 missense variants and 420del were identified in OCT1 in samples from four major ancestral groups [28] [29]. Since then, over 1000 single‐nucleotide polymorphisms (SNPs) have been identified [30], 22 of which have been related to treatment outcome for drugs transported by OCT1. Among these variants, 21 are located in the protein‐coding region causing amino‐acid substitutions, while one results in an amino‐acid deletion (p.M420del). Notably, the frequency of missense alleles in OCT1 is ancestry‐specific. European, African, and Latin American (Puerto Rican, Colombian and Mexican) populations present with higher variability than Asians and Pacific Islanders [30]. Six variants in OCT1 have a global allele frequency > 0.02 (Fig. 2.3, Table 2.3).
Many nonsynonymous polymorphisms of OCT1 have been functionally characterized in vitro. The uptake of the cation OCT1 substrate [3H] MPP+ was reduced in Xenopus oocytes expressing variants p.R61C, p.C88R, p.G401S, p.P341L, p.G220V, and p.G465R that were identified in a large sample of ancestrally diverse healthy subjects [28, 29]. Of the variants with significant functional differences from the reference OCT1, five (p.S14F, p.R61C, p.P341L, p.G401S, and p.G465R) occur at >1% allele frequency in at least one ancestral group. OCT1 variants p.P283L and p.R287G exhibit no uptake of either [14C] TEA or [3H] MPP+, although the protein level on the membrane of these variants is comparable to reference OCT1. The results suggest that residues Pro283 and Arg287 have a substantial role in substrate recognition or the transport cycle of OCT1 [2]. In another study, 12 OCT1 nonsynonymous variants were stably expressed in HEK cells, and metformin was used to characterize the uptake function of these variants [32]. Although the mRNA expression of these variants is comparable to reference allele, 7 OCT1 variants exhibit significantly reduced or lost metformin uptake. The GFP‐tagged p.G465R and p.R61C variants display abnormal localization on the plasma membrane [32]. Furthermore, the uptake of metformin is significantly reduced in cells expressing variants identified in Chinese and Japanese populations including p.Q97K, p.P117L, and p.R206C relative to the OCT1 reference [33].
FIGURE 2.3 Predicted secondary structure of OCT1 with most common (GAF > 0.02) missense variants highlighted. The group with the highest AF for each variant is shown. Created with TOPO2.
Due to a high level of evidence from many in vitro uptake studies and clinical pharmacogenomic studies on SLC22A1, the importance of OCT1 as an emerging transporter on drug disposition, response, and toxicity has been highlighted and discussed by the International Transporter Consortium (ITC) [34]. Many of these genetic associations have focused on the antidiabetic drug, metformin. However, studies of the effects of OCT1 polymorphisms on metformin pharmacokinetics and pharmacodynamics have been inconsistent. For example, while significant associations of missense OCT1 polymorphisms with metformin plasma concentrations were observed in several pharmacogenomics studies, other studies failed to observe such effects in either healthy subjects or patients with type 2 diabetes [2]. Positron emission tomography (PET)/computed tomography (CT) using 11C‐metformin showed that individuals who are carriers of the OCT1 reduced function variants, p.M420del and p.R61C, have decreased concentrations of metformin in the liver without changes in systemic plasma levels compared with individuals with reference OCT1 [2]. Additional associations between OCT1 polymorphisms and drug levels or response to prescription drugs other than metformin have been studied. These studies have demonstrated significant associations between reduced function nonsynonymous variants of SLC22A1 and the antimigraine drug, sumatriptan [2], the antinausea drug, ondansetron [35], and opiate analgesic drugs or their metabolites, including morphine and O‐desmethyltramadol [2]. More recently, OCT1 variants were also shown to significantly affect physiology and pathology. Human genome‐wide association study data indicate a possible correlation between metabolic phenotypes and OCT1 genotypes, which may be related to the disposition of its endogenous substrates, thiamine, and acylcarnitine [18, 20, 36].
TABLE 2.3 Common missense variants of SLC22 family cation and zwitterion transporters in major ancestral populations [31]
| Human gene | Protein name | Protein consequence | Allele frequency | ||||
|---|---|---|---|---|---|---|---|
| EUR | AFR | AMR | EAS | SAS | |||
| SLC22A1 | OCT1 | p.Leu160Phe p.Met408Val p.Met420del p.Arg61Cys p.Pro341Leu p.Val464Ile | 0.78 0.58 0.14 0.08 0.02 0.02 | 0.96 0.73 0.05 0.01 0.07 0.17 | 0.91 0.80 0.22 0.02 0.04 0.03 | 0.86 0.73 0.00 0.00 0.13 0.00 | 0.85 0.62 0.11 0.03 0.08 0.02 |
| SLC22A2 | OCT2 | p.Ser270Ala | 0.90 | 0.85 | 0.95 | 0.87 | 0.88 |
| SLC22A4 | OCTN1 | p.Ile306Thr p.Leu503Phe | 0.62 0.42 | 0.75 0.07 | 0.69 0.22 | 0.37 0.00 | 0.38 0.12 |
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