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Biomolecules
Special Issues
Organic Cation Transporters
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Organic Cation Transporters

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (28 March 2023) | Viewed by 5268

Special Issue Editors

Prof. Dr. Jürgen Brockmöller

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Guest Editor
Institute of Clinical Pharmacology, University Medicine Göttingen, Georg August University, Robert-Koch-Str. 40, D-37075 Göttingen, Germany
Interests: drug metabolism; drug membrane transport and clinical pharmacokinetics; pharmacogenetics and pharmacogenomics; biochemical pharmacology
Prof. Dr. Salvatore Cisternino

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Guest Editor
Faculté de Pharmacie, Hôpital Necker-Enfants Malades, Université Paris Cité, INSERM UMR-S 1144, 4, Avenue de l’Observatoire, 75006 Paris, France
Interests: blood–brain barrier; neurovascular unit; blood-retina barrier; drug transporters; brain drug delivery; SLC and ABC transporters; pharmacokinetics
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Special Issue Information

Dear Colleagues,

Looking at publication frequencies, research on organic cation transporters (OCTs) still seems to be outshined by research on organic anion transporters (OATs) and ABC transporters (ABCs) (https://pubmed.ncbi.nlm.nih.gov), although probably one-third of all low-molecular-weight drugs are organic cations. With this Special Issue of Biomolecules, we would like to promote progress and cooperation in OCT research. We are particularly looking for original contributions and reviews in the following four fields in OCT research:

1) All about biochemical pharmacology of OCTs. Notably, for the majority of organic cations even the genetic identity of the pharmacokinetically relevant OCTs has not yet been revealed.

2) Classical and advanced approaches in bioinformatics related to OCTs. That should allow a comprehensive understanding of substrate spectra of OCTs and molecular interactions between OCTs and their substrates.

3) Regulation of the expression and activity of organic cation transporters by genetics, epigenetics and environmental factors. Additionally, the organ-specific versus ubiquitous expression of OCTs is still not well understood. Improvements to this knowledge would help to understand variation in pharmacokinetics and in the therapeutics or adverse effects of cationic drugs.

4) More about the role OCTs play in the disposition of endogenous molecules and of molecules from microbial and plant metabolomes to which we are always exposed from nutrition and from our microbiomes in health and disease.

Of course, other suggestions and contributions to the understanding of OCTs are also welcome.

With best wishes,

Prof. Dr. Jürgen Brockmöller
Prof. Dr. Salvatore Cisternino
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • organic cation transporters
  • OCT
  • solute carriers
  • SLC
  • blood-brain barrier
  • pharmacokinetic modelling
  • structural biology
  • metabolomics
  • transcriptional regulation

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Published Papers (2 papers)

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21 pages, 6199 KiB  
Article
Atypical Substrates of the Organic Cation Transporter 1
by Kyra-Elisa Maria Redeker, Ole Jensen, Lukas Gebauer, Marleen Julia Meyer-Tönnies and Jürgen Brockmöller
Biomolecules 2022, 12(11), 1664; https://doi.org/10.3390/biom12111664 - 9 Nov 2022
Cited by 13 | Viewed by 2559
Abstract
The human organic cation transporter 1 (OCT1) is expressed in the liver and mediates hepatocellular uptake of organic cations. However, some studies have indicated that OCT1 could transport neutral or even anionic substrates. This capability is interesting concerning protein-substrate interactions and the clinical [...] Read more.
The human organic cation transporter 1 (OCT1) is expressed in the liver and mediates hepatocellular uptake of organic cations. However, some studies have indicated that OCT1 could transport neutral or even anionic substrates. This capability is interesting concerning protein-substrate interactions and the clinical relevance of OCT1. To better understand the transport of neutral, anionic, or zwitterionic substrates, we used HEK293 cells overexpressing wild-type OCT1 and a variant in which we changed the putative substrate binding site (aspartate474) to a neutral amino acid. The uncharged drugs trimethoprim, lamivudine, and emtricitabine were good substrates of hOCT1. However, the uncharged drugs zalcitabine and lamotrigine, and the anionic levofloxacin, and prostaglandins E2 and F2α, were transported with lower activity. Finally, we could detect only extremely weak transport rates of acyclovir, ganciclovir, and stachydrine. Deleting aspartate474 had a similar transport-lowering effect on anionic substrates as on cationic substrates, indicating that aspartate474 might be relevant for intra-protein, rather than substrate-protein, interactions. Cellular uptake of the atypical substrates by the naturally occurring frequent variants OCT1*2 (methionine420del) and OCT1*3 (arginine61cysteine) was similarly reduced, as it is known for typical organic cations. Thus, to comprehensively understand the substrate spectrum and transport mechanisms of OCT1, one should also look at organic anions. Full article
(This article belongs to the Special Issue Organic Cation Transporters)
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14 pages, 824 KiB  
Article
Stereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3
by Lukas Gebauer, Muhammad Rafehi and Jürgen Brockmöller
Biomolecules 2022, 12(10), 1507; https://doi.org/10.3390/biom12101507 - 18 Oct 2022
Cited by 4 | Viewed by 2199
Abstract
Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) [...] Read more.
Stereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters. Full article
(This article belongs to the Special Issue Organic Cation Transporters)
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