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progesterone, B‐estradiol, corticosterone Exogenous: verapamil, carvedilol, imipramine, cimetidine, metformin OCTN1 L‐ergothioneine, TEA Endogenous: L‐ergothioneine, L‐carnitine, acetylcholine Exogenous: cytarabine, amisulpride, ethambutol, ipratropium, gapapentin TEA Endogenous: L‐carnitine, acetylcarnitine, choline, acetylcholine, gamma‐butyrobetaine Exogenous: carvedilol, flecainide, lidocaine, verapamil, mitoxantrone, dipyridamole, doxorubicin OCTN2 L‐carnitine Endogenous: L‐carnitine, acetyl‐L‐carnitine, choline Exogenous: D‐carnitine, mildronate, ipratropium, etoposide, amisulpride TEA, verapamil Endogenous: L‐carnitine, acetylcarnitine Exogenous: clozapine, emetine, vinblastine, omeprazole, verapamil, B‐lactam antibiotics

      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

      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].

Schematic illustration of predicted secondary structure of OCT1 with most common (GAF greater than 0.02) missense variants highlighted.
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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