Investigating the Involvement of the Sulfotransferase Pathway in Drug-induced Skin Rash
Bibliographic record
Abstract
Circumstantial evidence suggests that most idiosyncratic drug reactions are caused by chemically reactive metabolites of the drug that covalently binds to proteins. The skin is a major target of idiosyncratic reactions; however, drug metabolism in the skin is limited. One exception is the presence of relatively high sulfotransferase activity in human skin. For example, nevirapine-induced skin rash is caused by a reactive benzylic sulfate formed in the skin. The working hypothesis is that the serious skin rashes caused by other drugs involve reactive sulfate metabolites formed in the skin. Trimethoprim, lamotrigine, valdecoxib, and sertraline have the potential to produce reactive sulfate metabolites that may be responsible for drug-induced skin rash. Anti-drug antibodies against trimethoprim, lamotrigine, and valdecoxib were made to study covalent binding of the drug to proteins. Brown Norway rats were treated with these drugs, and their liver and skin proteins were immunoblotted to look for covalent binding. No covalent binding of any of these drugs was detected in the skin, but covalent binding of trimethoprim was detected in the liver. The immunoassay may not be sufficiently sensitive to detect covalent binding in the skin, or binding may be limited to human skin. The sulfates of hydroxy-trimethoprim and lamotrigine-N-oxide, which are metabolites of these drugs, were chemically synthesized, and both were found to be chemically reactive. Surprisingly, even hydroxy-trimethoprim itself had sufficient reactivity to covalently bind to proteins in vitro. Dr. Liu, our collaborator at the University of Toledo, tested whether hydroxy-trimethoprim, lamotrigine-N-oxide, hydroxy-valdecoxib or hydroxy-sertraline were substrates of human sulfotransferases. He found that lamotrigine-N-oxide was a substrate for several human sulfotransferases, while hydroxy-trimethoprim was only a substrate for the fetal sulfotransferase SULT1C4, and hydroxy-valdecoxib and hydroxy-sertraline were not substrates for human sulfotransferases. That implies that the rashes caused by valdecoxib and sertraline are not due to a sulfate metabolite. Given that hydroxy-trimethoprim is only a substrate for a fetal sulfotransferase but is weakly reactive, it may be responsible for trimethoprim rashes. The rash caused by lamotrigine is likely due to the N-O-sulfate; however, detection of covalent binding in skin would have strengthened the evidence for this hypothesis.
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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".