Differential Specificity of the Human and Mouse Multidrug Resistance Protein 4 (MRP4) Orthologs for Arsenic Metabolites
Bibliographic record
Abstract
An estimated 160 million people world‐wide are exposed to levels of arsenic in their drinking water higher than the limit of 10 ppb (10 μg/L) set by the World Health Organization. Arsenic is a Group 1 (proven) human carcinogen which causes skin, lung, and bladder tumors, and is associated with numerous other adverse health effects, including neuropathy and cardiovascular dysfunctions. Multidrug resistance proteins (MRPs/ABCCs) mediate the cellular efflux of a chemically diverse array of endogenous and xenobiotic metabolites. Substrates include glutathione (GSH) conjugates of inorganic and methylated arsenic species and dimethylarsinic acid (DMA V ). Unlike in humans, arsenic is a poor carcinogen in rodents, requiring at least 100‐fold higher doses for tumour induction. Differences in toxicokinetics between humans and other species are also well documented. We have shown that human MRP4 (hMRP4) reduces the cytotoxicity and cellular accumulation of inorganic and methylated arsenic species, and hMRP4‐enriched membrane vesicle transport studies identified the GSH conjugate of the highly toxic methylated arsenic metabolite monomethylarsonous acid (MMA III ), MMA(GS) 2 , and the major human urinary metabolite DMA V as the transported forms. The objective of the current study was to determine if mouse Mrp4 (mMrp4) conferred resistance to and/or transported the same arsenic species as hMRP4. HEK293 clonal cell lines stably expressing mMrp4 were established and used in cytotoxicity assays. Our results showed that mMrp4 did not confer resistance to any of the arsenic species tested [arsenite (As III ), arsenate (As V ), MMA III , monomethylarsonic acid (MMA V ), dimethylarsinous acid (DMA III ) or DMA V ]. Studies with mMrp4‐enriched membrane vesicles showed that unlike hMRP4, mMrp4 did not transport MMA(GS) 2 or DMA V . Thus, under the conditions tested, arsenicals are not substrates for mMrp4. These results suggest that hMRP4/mMrp4 could contribute to differences in arsenic toxicokinetics between humans and mice. Furthermore, Mrp4/Abcc4(−/−) mice are unlikely to be a relevant model for understanding the in vivo contribution of hMRP4 to arsenic detoxification and elimination. Support or Funding Information Canadian Institutes of Health Research, Alberta Innovates Health Solutions, Faculty of Medicine and Dentistry, University of Alberta
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".