Re‐investigation into the Ligand Selectivity of OAT2
Bibliographic record
Abstract
There are discrepancies in the literature regarding ligand selectivity of organic anion transporter 2 (OAT2). The purpose of this study was to re‐examine the interaction of ligands with both transcript variants of OAT2 since it is not known whether they are functionally distinct. The two splice variants of human OAT2 (OAT2‐TV1 and OAT2‐TV2) were stably transfected into three cell lines (CHO, HEK and MDCK), and the interaction of previously identified substrates and inhibitors was assessed. Expression of both transcript variants was confirmed at the mRNA level, but only OAT2‐TV1 protein was detected at the cell surface. Uptake of penciclovir was ~1.5‐20 fold higher in OAT2‐TV1 cells compared to control, but para‐aminohippurate (PAH), estrone sulfate (ES), succinate and glutarate transport was not observed. Eight Krebs cycle intermediates (1mM) failed to cis‐inhibit penciclovir uptake. Conversely, cis‐inhibition by a structurally diverse set of xenobiotic drugs, including anions, cations and neutral compounds suggests that OAT2‐TV1 is broadly selective. Treatment of cells with sulfo‐NHS‐SS biotin inhibited penciclovir transport. Co‐treatment of cells with furosemide along with sulfo‐NHS‐SS biotin ameliorated transport activity, suggesting that lysine residue(s) line the ligand binding surface. These results show that OAT2‐TV2 is non‐functional in mammalian cells, likely due to a trafficking defect. Additionally, lack of mediated transport or cis‐inhibition by several previously reported compounds highlights the necessity to re‐examine ligand selectivity of OAT2‐TV1 to better understand its importance in pharmacokinetics. Supported by CIHR and NSHRF.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".