Application of quantitative structure-toxicity relationships to quinone-induced cellular oxidative stress
Bibliographic record
Abstract
Oxidative stress can be defined as a level of reactive oxygen species (ROS) formation that overcomes the threshold of cellular detoxification processes, which results in cellular damage. In chapter 1 of this study, we first examined intracellular sources (organelles) for "natural" formation of ROS, by using chemicals that are endogenously found. We determined that substrates metabolized by enzymes associated with mitochondria, peroxisomes, and endoplasmic reticula, formed ROS that lead to cytotoxicity, which became enhanced after catalase inhibition. A correlation between ROS formation and cytotoxicity was found, which led us to study this correlation using xenobiotics. In chapter 2, we examined ROS formation and cytotoxicity induced by a congeneric family of quinones and used quantitative structure-toxicity relationships (QSTRs) to analyze these results for both isolated rat hepatocytes and rat PC12 cells. A two dimensional (2D) QSTR or Hansch analysis was used to derive (multiple) linear regression equations for the cytotoxicity towards both cell types. This analysis identified electron affinity (or electrophilicity) of the quinone as the critical parameter responsible for the observed cytotoxicity and ROS formation. In chapter 3 we determined the effect of inhibiting NAD(P)H:Quinone Oxidoreductase (NQO), involved in a 2e- quinone reduction, with dicumarol on quinone cytotoxicity and ROS formation. Interestingly, apparent NQO inhibition affected hepatocyte susceptibility to quinones much more than PC 12 cells, which had little NQO activity relative to hepatocytes. Some quinones formed more ROS and were more cytotoxic to NQO inhibited hepatocytes, whilst other quinones were not affected. We derived 2D and three-dimensional (3D) QSTRs and found that both approaches yielded statistically significant models; but the 3D QSTR models were much more accurate. In the last chapter, we identified the bicarbonate anion (HCO3- ) as an important modulator of ROS formation and cytotoxicity. The effect of HCO3 - was titratable, and increased the cytotoxicity of redox cycling quinones, but not alkylating quinones. A carbonate radical mediated cytotoxic mechanism is proposed.
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".