Impact of the loss of slc43a3 on 6-mercaptopurine absorption and tissue distribution in mice
Bibliographic record
Abstract
6-Mercaptopurine (6-MP) is a nucleobase analog used in the therapy of acute lymphoblastic leukemia and inflammatory bowel disease. It is associated with numerous side effects including myelotoxicity, hepatotoxicity, and gastrointestinal complications, which can lead to patient adherence issues or discontinuation of treatment. This is further complicated by the wide variability in plasma levels of 6-MP and the therapeutic response to a standard dose. Although a number of enzyme polymorphisms have been linked to therapeutic response, it is unclear what factors underlie the variability in plasma levels. We have established that SLC43A3-encoded equilibrative nucleobase transporter 1 mediates the transport of 6-MP into cells in both mice and humans. To determine whether this transporter is critical for 6-MP absorption and biodistribution, we examined the effect of the genetic deletion of slc43a3 in mice on the absorption and tissue distribution of orally administered 6-MP. A high-performance liquid chromatography method was developed to measure tissue levels of 6-MP and its key metabolites, 6-methylmercaptoprine, 6-thiourate, and 6-thioguanine nucleotides. The results of this study show that loss of slc43a3 dramatically reduces the absorption of 6-MP from the gastrointestinal tract and attenuates the levels achieved in peripheral tissues. Furthermore, the loss of slc43a3 decreases the tissue:blood concentration ratios of 6-MP and its metabolites, particularly in those tissues that show high levels of expression of slc43a3, such as the heart and lungs. Therefore, it is possible that differences in SLC43A3 expression in humans may contribute to the variability seen in 6-MP plasma levels and therapeutic response. SIGNIFICANCE STATEMENT: The loss of slc43a3 in mice dramatically reduces the absorption and the biodistribution of the chemotherapeutic drug 6-mercaptopurine. These data suggest that variations in SLC43A3 expression in humans may contribute to the variability in plasma levels that have been reported when using this drug therapeutically.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".