Investigation of the Mechanism of Idiosyncratic Drug-induced Liver Injury
Bibliographic record
Abstract
Idiosyncratic drug reactions represent a special problem because of their unpredictable nature, and idiosyncratic drug-induced liver injury (IDILI) is a major reason for drug withdrawal. Our objective was to investigate the mechanism of IDILI caused by isoniazid and amodiaquine. Isoniazid-induced liver injury was believed to be due to bioactivation of N-acetylhydrazine, a metabolite of isoniazid; however, that conclusion was based on a rat model with characteristics very different from isoniazid-induced IDILI in patients. I found that isoniazid is directly bioactivated and covalently binds to hepatic proteins; furthermore, mice are a better model for human isoniazid metabolism than rats. We found that mild isoniazid-induced liver injury in patients is associated with an increase in Th17 cells and IL-10-producing T cells. I also found anti-isoniazid antibodies in the serum of patients with isoniazid-induced liver failure. These results suggest that isoniazid-induced IDILI is immune-mediated rather than metabolic idiosyncrasy as previously believed. Treatment of mice with isoniazid failed to lead to significant liver injury. We postulated that this was because of immune tolerance; however, attempts to develop an animal model using mice with impaired immune tolerance were unsuccessful. Treatment of mice with amodiaquine resulted in mild liver injury that resolved despite continued treatment similar to the more common type of IDILI observed in humans. In this model, liver injury is immune-mediated with the initial injury mediated by natural killer cells, while the resolution of liver injury appears to involve the adaptive immune system because resolution was slower in Rag-/- mice. In summary, my studies have resulted a change in what is considered to be the mechanism of isoniazid-induced IDILI. We have developed an animal model of mild immune-mediated amodiaquine-induced liver injury, but we failed to develop a valid animal model of severe IDILI, most likely because the dominant immune response in the liver is tolerance.
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How this classification was reachedexpand
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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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 teacher head, 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".