Drug-Induced Protein Free Radical Formation Is Attenuated by Unsaturated Fatty Acids by Scavenging Drug-Derived Phenyl Radical Metabolites
Bibliographic record
Abstract
Aromatic amine drugs like aminoglutethimide (AG) and related congeners have been shown to produce phenyl radicals through metabolism by myeloperoxidase (MPO)/H(2)O(2), which has been proposed to play a role in drug-induced agranulocytosis. AG has also been shown to induce MPO protein radical formation, but the ultimate fate of these metabolically generated phenyl radicals is still unknown. We tested the reactivity of linoleic acid (LA) and GSH with aniline-based compounds in the presence of horseradish peroxidase (HRP)/H(2)O(2) by measuring oxygen consumption. We found a qualitative correlation between drugs or xenobiotics that formed phenyl radical metabolites with the cooxidation of LA. Most compounds that reacted with LA did not react with GSH. Furthermore, an AG-derived phenyl radical was detected by EPR spin-trapping with MNP (2-methyl-2-nitrosopropane), in a reaction containing AG and HRP/H(2)O(2); these spectra were attenuated in the presence of LA and docosahexaenoic acid (DHA) indicating that phenyl radical scavenging occurred. Since it has been proposed that the phenyl radical metabolite leads to protein radical formation on MPO, we investigated the effect of LA and DHA in immuno-spin trapping experiments with MPO-containing HL-60 cell lysate. Using anti-DMPO, a protein radical was detected on a putative MPO fragment from the reaction of DMPO, AG, and glucose/glucose oxidase. When LA or DHA was included in this reaction, protein radical formation was significantly inhibited. Our results show that certain polyunsaturated fatty acids (PUFAs) act as scavengers of aromatic amine drug-derived phenyl radicals which in turn prevent protein radical formation. However, the interaction of phenyl radical drug metabolites with PUFAs will be dictated by their relative concentrations compared to those of other targets. Most importantly, it is possible to differentiate peroxidase substrates that generate phenyl radical metabolites from N-centered radicals on the basis of their reactivity toward GSH vs PUFAs, and PUFAs are targets for metabolically generated phenyl radicals.
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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) | 0.001 | 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".