Control of hepatocyte DNA synthesis by intracellular pH and its role in the action of tumor promoters
Why this work is in the frame
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Bibliographic record
Abstract
The mechanisms of tumor promotion in liver by various xenobiotics of diverse structure are not well understood. However, these tumor promoters share the ability to exert growth-stimulatory effects on hepatocytes. Our laboratory has been utilizing normal rat hepatocytes under defined conditions of primary cultures, to investigate growth-stimulatory actions of liver tumor promoters. We have shown that most, if not all, of the liver tumor promoters tested stimulate hepatocyte DNA synthesis when added in combination with epidermal growth factor (EGF), insulin, and glucocorticoids. In the present study, we sought evidence for the role of the Na(+)/H(+) antiporter and cytoplasmic alkalinization in the direct growth-stimulatory actions of tumor promoters on hepatocytes. Hepatocytes cultured under conditions (bicarbonate-buffered medium) where intracellular pH (pH(i)) was independent of extracellular pH (pH(e)), EGF- and insulin-stimulated rates of DNA synthesis were unaffected by modest changes in pH(e). However, under conditions (HEPES-buffered medium) where pH(i) varied in a linear fashion with pH(e), rates of EGF- and insulin-stimulated DNA synthesis were highly dependent on pH(e). Similarly, 12-O-tetradecanoylphorbol-13-acetate (TPA) and alpha-hexachlorocyclohexane (HCH)-stimulated DNA synthesis were pH(e)-dependent but were stimulatory over different pH(e) ranges, suggesting that these promoters may act by distinct mechanisms. Chemicals that are capable of inducing rapid cytoplasmic alkalinization, ammonium chloride (1 and 15 mM) and monensin (0.5 microM), were found to stimulate hepatocyte DNA synthesis. The role of the Na(+)/H(+) antiport in controlling pH(i) of hepatocytes was demonstrated by artificially acidifying 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein acetoxymethyl (BCECF)-loaded isolated hepatocytes with 20 mM sodium acetate and the use of specific inhibitors. Amiloride and its analogues inhibited pH(i) recovery from the acid load in a dose dependent manner and the relative potency of these inhibitors paralleled their K(i) values for the Na(+)/H(+) antiport. At concentrations that stimulate hepatocyte DNA synthesis, some liver tumor promoters phenobarbital (PB) and HCH, were found to cause a rapid rise pH(i) in isolated hepatocytes which was sensitive to amiloride and its analogues. Taken together, our data suggest that activation of Na(+)/H(+) antiport activity may be one mechanism whereby some liver tumor promoters stimulate hepatocytes DNA synthesis. This study has implications for the mechanisms of tumor promotion in liver carcinogenesis.
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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 | 0.001 | 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) | 0.000 | 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