Role of NADPH:cytochrome P450 reductase in RH1 activation
Notice bibliographique
Résumé
5851 RH1 is a novel diaziridinylbenzoquinone bioreductive agent that has recently entered phase 1 clinical trials. It is an excellent substrate for the obligate two electron-reducing enzyme NQO1 (DT-diaphorase), and studies have demonstrated a relationship between NQO1 expression levels and drug response. It has been proposed that RH1 may be an effective NQO1-directed antitumor agent for the therapy of cells with elevated NQO1 activity. However, bioreductive agents may also be substrates for other reducing enzymes such as the 1-electron reducing enzyme, NADPH-cytochrome P450 reductase (P450 reductase), and therefore the role of this reducing enzyme in activating RH1 was examined. RH1 reduction by purified P450 reductase yielded a very strong electron paramagnetic resonance (EPR) signal, suggesting that RH1 could be reduced by this enzyme. Spectroscopic studies monitoring the disappearance of NADPH when RH1 was incubated with purified P450 reductase or NQO1 confirmed that this agent can be a substrate for either enzyme, and that under aerobic conditions RH1 undergoes redox cycling. To examine whether P450 reductase can play a role in activating RH1 in tumor cells, we used T47D human breast cancer cells and T47D cells transfected with the P450 reductase gene which have 20-fold increased P450 reductase activity. Pretreatment of the transfected T47D cells with the P450 reductase inhibitor, diphenyliodonium chloride (DPIC), did not inhibit RH1 cytotoxicity. In contrast, pretreatment of the transfected T47D cells with the NQO1 inhibitor, dicoumarol, significantly inhibited the of cytotoxicity of RH1, confirming the role of NQO1 as an activator of this agent. However, if the transfected cells were pretreated with both inhibitors there was additional inhibition of cytotoxicity compared with dicoumarol alone, suggesting that in the absence of NQO1 activity, high levels of P450 reductase activity could contribute to RH1 activation and cytotoxicity. A similar study in the parental T47D cells showed that pretreatment with both enzyme inhibitors did not result in greater inhibition of cytotoxicity than pretreatment with dicoumarol alone. These results suggest that although P450 reductase can reduce RH1, NQO1 is the major activator of this agent. and P450 reductase likely does not play a role in RH1 activation at normal cellular levels of this enzyme. (Supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society and the CancerCare Manitoba Foundation)
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».