Regulation of the ATP Hydrolysis and Transport Cycles of the P‐Glycoprotein Multidrug Transporter by Sterols and Phospholipids
Bibliographic record
Abstract
Multidrug resistance in many human cancers is linked to expression of the P‐glycoprotein multidrug transporter (Pgp, ABCB1), an ABC protein that exports many structurally diverse compounds from cells. Since Pgp pumps lipophilic substrates out of the membrane, the lipid environment plays an important role in regulating its activity. Using purified Pgp functionally reconstituted into proteoliposomes, we investigated the interaction of Pgp with sterols, and the effect of various defined phospholipids and sterols on basal ATP hydrolysis, Hoechst 33342‐stimulated ATP hydrolysis, and Hoechst 33342 transport. Fluorescence quenching showed that Pgp interacted with the fluorescent sterols, dehydroergosterol (DHE) and NBD‐cholesterol, with high affinity. Cholesterol hemisuccinate (CHS) greatly stabilized the basal ATPase activity of Pgp in detergent and proteoliposomes of some phospholipids, but DHE did not. CHS also had a pronounced effect on thermal unfolding of Pgp, as determined by CD spectroscopy. The stabilizing effects of CHS on drug‐stimulated ATP hydrolysis and drug transport were strongly dependent on bilayer phospholipid composition, and were distinct from those noted for basal ATP hydrolysis. This suggests that the basal ATPase and drug transport cycles of Pgp are distinct, and regulated differently by the lipid environment. Funded by the Canadian Cancer Society (grant #700248).
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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) | 0.000 | 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 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".