Selenide stimulates the biliary excretion of arsenic in human HepaRG cells
Bibliographic record
Abstract
Arsenic is classified by the International Agency for Research on Cancer as a Group I (proven) human carcinogen causing lung, skin and bladder cancer. Conservative estimates suggest that between 92‐220 million people worldwide are exposed to arsenic at levels exceeding the World Health Organization guideline of 10 µg/L. In animal models arsenic and selenium are mutually protective via the formation and biliary excretion of the seleno‐bis (S‐glutathionyl) arsinium ion [SeAs(GS) 2 ] ‐ , which allows for the fecal elimination of both compounds. Consistent with this, selenium deficiency in humans living in arsenic endemic regions is associated with an increased risk of arsenic induced disease. These observations have led to the initiation of human selenium supplementation trials. Despite these ongoing trials in arsenic endemic regions, the influence of selenium on human hepatic handling of arsenic is not adequately understood. Furthermore, supplementation trials have utilized different chemical forms of selenium with unknown influence on efficacy. In the liver, multidrug resistance protein 2 (MRP2/ABCC2) transports arsenic metabolites, including [SeAs(GS) 2 ] ‐ into bile, and the related MRP4 (ABCC4) transports other arsenic metabolites into hepatic sinusoids. We hypothesized that selenium increases biliary excretion of arsenite (As III ) from HepaRG cells, an immortalized cell line used as a surrogate for primary human hepatocytes. Our objective was to study the influence of selenite (Se IV ), selenide (HSe ‐ ), methylselenocysteine (MeSeCys) and selenomethionine (SeMet) on arsenic efflux from HepaRG cells. HepaRG cells were untreated, or treated with 1 µM As III ± selenium (Se IV , HSe ‐ , MeSeCys or SeMet) for 48 hr. Then crude membrane preparations of HepaRG cells were subjected to immunoblots to evaluate the presence of MRP2 and MRP4 proteins. MRP2 function was evaluated by 5(6)‐carboxy,2’,7’ dichlorofluorescein (CDF) accumulation in canalicular networks by fluorescence microscopy. Transport across sinusoidal and canalicular membranes was measured after treatment of HepaRG cells with 1 µM 73 As III ± selenium (Se IV , HSe ‐ , MeSeCys or SeMet) using B‐CLEAR® technology. Biliary excretion indices (BEIs) were calculated to quantify the extent of arsenic export into bile. Transport was re‐evaluated under conditions expected to inhibit efflux. MRP2 and MRP4 proteins are present in HepaRG cells. MRP2 levels increased after treatment with As III ± HSe ‐ , whereas MRP4 levels increased after treatment with 1 µM As III . CDF accumulated in canalicular networks, suggesting the presence of functional MRP2. At a 5 minute time point, the BEI of 73 As III alone was 13±7%, which was stimulated by the presence of HSe ‐ (BEI=31±7%). Biliary excretion of 73 As III was lost in the presence of other selenium forms, but sinusoidal efflux of 73 As III was stimulated by MeSeCys. Reduction of hepatobiliary transport was observed at 4 ∘ C as well as with inhibitors of glutathione synthesis and MRPs. Arsenic underwent biliary excretion in HepaRG cells, and this was stimulated by HSe ‐ , the biologically active form of selenium metabolism. Arsenic hepatobiliary transport by MRP2 is temperature and glutathione dependent. This work advances understanding of selenium effects on arsenic handling by human liver.
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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 | 0.000 |
| 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".