19‐(S/R)Hydroxyeicosatetraenoic Acid is a Novel Endogenous Inhibitor of Cytochrome P450 1B1 in Enantioselective Manner
Bibliographic record
Abstract
Purpose CYP1B1 is known to contribute to the pathogenesis of several diseases such as cancer and cardiac hypertrophy by forming the toxic metabolites. We recently reported that the arachidonic acid metabolite, 19(S/R)hydroxyeicosatetraenoic (HETE) acid, confers cardioprotection against cardiac hypertrophy by inhibiting the formation of cardiotoxic metabolites, midchain HETEs, known to be formed by CYP1B1. This raised the question whether 19(S/R)‐HETE can directly inhibit the CYP1B1. Methods Human ventricular cardiomyocytes, RL‐14 cells were treated with vehicle or 10 μM Ang II in the absence and presence of 20 μM 19(R)‐HETE or 19(S)‐HETE for 24 h. Gene and protein expression were measured using real‐time PCR and Western blot analysis, respectively. The level of mid‐chain HETEs was determined using liquid chromatography–mass spectrometry (LC/MS). The O‐dealkylation rate of 7‐ethoxyresorufin (EROD) by recombinant human CYP1B1 was measured in the absence and presence of 19(R)‐HETE or 19(S)‐HETE. Results The results showed that both 19(R)‐HETE and 19(S)‐HETE significantly decreased the metabolite formation rate of midchain HETEs, namely 8‐, 9‐, 12‐ and 15‐HETE compared to control group. Nonlinear regression analysis and comparisons showed that the mode of inhibition for 19(R)‐HETE and 19(S)‐HETE is non‐competitive inhibition of CYP1B1 enzyme. Dixon plots showed that 19(R)‐HETE and 19(S)‐HETE have Ki values of 89.1 and 37.3 nM, respectively. The Ki values of both enantiomers showed that the S‐enantiomer is more potent than the R‐enantiomer by approximately 2.4 fold. Conclusion The current study suggests that 19( R )‐HETE and 19( S )‐HETE could be considered a novel therapeutic modality in the treatment of cardiac hypertrophy, and cancer. Moreover, given that a non‐competitive inhibitor might bind to the enzyme regulatory region, 19( R )‐HETE and 19( S )‐HETE could be the focus for unraveling the obscure mechanisms of CYP1B1 enzymatic reaction. Support or Funding Information This work was supported by a grant from CIHR to A.O.S.E. S.M.S. is the recipient of Alberta Innovates Graduate Student Scholarship.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
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".