Comparison of rat and human cytochrome P450 (CYP) sources of<i>N</i>-alkylprotoporphyrin IX. Formation after interaction with porphyrinogenic xenobiotics: studies with cDNA-expressed single CYP enzymes
Bibliographic record
Abstract
1. The porphyrinogenicity of certain xenobiotics is due to mechanism-based inactivation of selected cytochrome P450 (CYP) enzymes, with concurrent formation of N-alkylprotoporphyrins (N-alkylPPs), which disrupt control of haem biosynthesis. An ambiguity arises when extrapolating results obtained with such porphyrinogenic xenobiotics in animals to humans owing to species' differences in CYP enzymes. The objective was to use cDNA-expressed individual rat CYP enzyme preparations in microsomes prepared from baculovirus-infected insect cells to determine which rat CYP enzymes were the source of N-alkylPPs after interaction with three porphyrinogenic xenobiotics and to compare the results with formation of N-alkylPPs in individual human CYP enzyme orthologues. 2. A sensitive fluorometric technique was employed to quantitate N-alkylPP formation after interaction of individual CYP enzymes with a porphyrinogenic xenobiotic. 3. N-alkylPP formation was found following the interaction of three porphyrinogenic xenobiotics with CYP1A2, 2B1, 2C6, 2C11 and 3A2, in amounts ranging from 0.45 to 0.07 nmol N-alkylPP nmol(-1) CYP. The results obtained with rat CYP1A2, 2C6, 2C11 and 3A2 were compared with those previously obtained with the human CYP orthologues 1A2, 2C9 and 3A4. 4. Some results corresponded while others did not, reinforcing a previous recommendation that when dealing with xenobiotics whose porphyrinogenicity depends upon interaction with CYP enzymes resulting in N-alkylPP formation, animal experiments should be augmented with studies using human CYP preparations.
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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 | 0.000 | 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".