Prostaglandin H synthase (PHS)‐1/2‐dependent oxidative DNA damage and cytotoxicity caused by neurotransmitters, their precursors and metabolites
Bibliographic record
Abstract
PHS‐1 and PHS‐2 are implicated in neurodegeneration, but the mechanism is unclear. Neurotransmitters, their precursors and metabolites may serve as substrates for PHS‐1/2‐dependent bioactivation in the brain to free radicals that generate potentially neurotoxic reactive oxygen species ( ROS ). To assess this hypothesis, ovine PHS‐1 was incubated in vitro with DNA and dopamine ( DA ) or its precursor or metabolites. DA (p<0.05), L‐dihydroxyphenylalanine ( L‐DOPA ) (p<0.05) and dihydroxyphenylacetic acid ( DOPAC ) (p<0.05) were oPHS‐1 substrates, resulting in PHS‐dependent ROS formation that initiated DNA oxidation, quantified as 8‐oxo‐2′‐deoxyguanosine. CHO‐K1 cell lines expressing human PHS‐2 ( hPHS‐2 ) and untransformed CHO‐K1 cells were used to investigate hPHS‐2‐dependent cytotoxicity. PHS activity, quantified by the conversion of arachidonic acid ( AA ) to prostaglandin E2, was up to 40‐fold higher in hPHS‐2 cells compared to untransformed CHO‐K1 cells and activities were reduced by withholding AA (p<0.01). Cytotoxicity, measured by lactate dehydrogenase release, was higher in hPHS‐2 cells treated with DA, L‐DOPA, DOPAC or homovanillic acid versus vehicle control after a 6 hour incubation (p<0.001). AA‐activation increased hPHS‐2 cytotoxicity (p<0.05), while cytotoxicity was lower in untransformed CHO‐K1 cells (p<0.05). These results show that DA, its precursor and metabolites are substrates for PHS‐1/2‐dependent bioactivation, causing ROS‐mediated oxidative DNA damage and cytotoxicity. This mechanism may be involved in neurodegenerative changes associated with aging and drugs like amphetamines, which initiate neurotransmitter release. [Support: CIHR, CIHR/Rx&D HRF]
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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 | 0.000 |
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".