A naturally occurring mutation in MRP1 results in a selective decrease in organic anion transport and in increased doxorubicin resistance
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Bibliographic record
Abstract
The human 190 kDa multidrug resistance protein, MRP1, is a polytopic membrane glycoprotein that confers resistance to a wide range of chemotherapeutic agents. It also transports structurally diverse conjugated organic anions, as well as certain unconjugated and conjugated compounds, in a reduced glutathione-stimulated manner. In this study, we characterized a low-frequency (<1%) naturally occurring mutation in MRP1 expected to cause the substitution of a conserved arginine with serine at position 433 in a predicted cytoplasmic loop of the protein. Transport experiments with membrane vesicles prepared from transfected human embryonic kidney cells and HeLa cells revealed a two-fold reduction in the ATP-dependent transport of the MRP1 substrates, leukotriene C4 (LTC4) and oestrone sulphate. Kinetic analysis showed that this reduction was due to a decrease in Vmax for both substrates but Km was unchanged. In contrast, 17beta-oestradiol-17beta-(D-glucuronide) transport by the Arg433Ser mutant MRP1 was similar to that by wild-type MRP1. Fluorescence confocal microscopy showed that the mutant MRP1 was routed correctly to the plasma membrane. In contrast to the reduced LTC4 and oestrone sulphate transport, stably transfected HeLa cells expressing Arg433Ser mutant MRP1 were 2.1-fold more resistant to doxorubicin than cells expressing wild-type MRP1, while resistance to VP-16 and vincristine was unchanged. These results provide the first example of a naturally occurring mutation predicted to result in an amino acid substitution in a cytoplasmic region of MRP1 that shows an altered phenotype with respect to both conjugated organic anion transport and drug resistance.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 it