Cystathionine Gamma‐Lyase Inhibition in Primary Human Hepatocytes Affects the Production of Hydrogen Sulfide Biomarkers through the Transsulfuration Pathway
Bibliographic record
Abstract
Hydrogen sulfide (H 2 S) has been identified as a neurotransmitter involved in smooth muscle dilation and thus, may have cardioprotective effects in‐vivo. The transsulfuration enzymes, cystathionine beta‐synthase (CBS) and cystathionine gamma‐lyase (CSE), produce the majority of endogenous H 2 S concurrent with the formation of lanthionine (lan) and homolanthionine (hlan) biomarkers. We compared transsulfuration pathway kinetics and H 2 S biomarkers in primary human hepatocytes with and without functionality of enzyme CSE. CSE was inhibited by 1000 µM propargylglycine (PAG) and metabolic fluxes were determined using [U‐ 13 C 5 ] L‐methionine and (3,3 D2) L‐cysteine precursors. Methionine cycle kinetics and rate of homocysteine production were not affected by the addition of PAG. In the presence of PAG, cystathionine was accumulated in cells and media (P<0.001). Intracellular hlan concentration and fractional synthesis rates (FSR) were higher in untreated cells compared to cells with CSE inhibited (P<0.041), while in media hlan concentration was 50% less due to PAG inhibition (P<0.025). In the presence of PAG, lan concentration in cells and media exceeded those of untreated cells (P<0.012). The inhibition of CSE in primary hepatocytes greatly decreased the production of H 2 S biomarker hlan, while lan production was not affected. These results support in‐vitro studies indicating that CSE is the primary enzyme in hlan production while CBS produces the majority of lan. (Supported by NIH DK072398 and CIHR MOP133505).
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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".