MP68-16 XENOBIOTIC METABOLISM OF ABIRATERONE ACETATE AND GLUCOCORTICOIDS BY THE GUT MICROBIOTA
Notice bibliographique
Résumé
You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II (MP68)1 Apr 2019MP68-16 XENOBIOTIC METABOLISM OF ABIRATERONE ACETATE AND GLUCOCORTICOIDS BY THE GUT MICROBIOTA Kamilah Abdur-Rashid*, Shiva Nair, Ryan Chanyi, Joseph Chin, and Jeremy Burton Kamilah Abdur-Rashid*Kamilah Abdur-Rashid* More articles by this author , Shiva NairShiva Nair More articles by this author , Ryan ChanyiRyan Chanyi More articles by this author , Joseph ChinJoseph Chin More articles by this author , and Jeremy BurtonJeremy Burton More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000557031.40448.62AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Testosterone and dihydrotestosterone (DHT) stimulate the growth of prostate cancer by activating androgen receptors. Androgen deprivation therapy (ADT), the first line of systemic treatment, aims to decrease circulating androgens to castrate levels; however, castration resistant prostate cancer (CRPC) can develop. Abiraterone acetate (AA), an inhibitor of androgen synthesis, in combination with supportive glucocorticoids are used to treat CRPC. Many drugs are orally ingested and pass through the gastrointestinal tract, however, the dense bacterial population in the gut is often overlooked. We hypothesize that AA can modify the composition of the gut microbiota and gut bacteria can transform glucocorticoids into compounds that can activate androgen receptors. METHODS: A chemostat gut model was inoculated with human feces and exposed to physiological doses of AA. Samples were analyzed by culture-dependent and -independent methodologies. Bacterial isolates that increased in abundance upon exposure to AA were tested on agar containing AA. Secondly, Clostridium scindens, a corticosteroid-utilizing gut bacterium with known androgenic-producing abilities, were exposed to various clinically relevant glucocorticoids (prednisone, prednisolone and dexamethasone). The metabolic products were measured by liquid chromatography-mass spectrometry and bacterial gene expression by quantitative PCR. A yeast-based human androgen receptor assay was also used to detect the biotransformation of glucocorticoids for potential activation by bacterial metabolites. RESULTS: The bacterial composition of the gut model changed when exposed to AA. Select bacterial isolates were also able to utilize AA as a sole carbon source. C. scindens was found to metabolize prednisone, prednisolone and dexamethasone, possibly using machinery encoded on the desABCD operon. Gene expression analysis revealed increased expression of: desA by 8-fold; desB by 5.2-fold; desC by 4.8-fold; and desD by 2.6-fold. DHT-like activity on human androgen receptor assay increased significantly with C. scindens incubation with prednisone (3.6±0.8×10−9M) but not with prednisolone (no detectable activation) or dexamethasone (no detectable activation). CONCLUSIONS: These results suggest that we may need to consider the role of the gut microbiota in the treatment of CRPC. Bacterial interactions may change the pharmaceutical properties of drugs such as AA. Prednisone, co-administered with AA, can also be metabolized into androgenic compounds, which may play a part in CRPC treatment failure. Source of Funding: none London, Canada© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e981-e981 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kamilah Abdur-Rashid* More articles by this author Shiva Nair More articles by this author Ryan Chanyi More articles by this author Joseph Chin More articles by this author Jeremy Burton More articles by this author Expand All Advertisement PDF downloadLoading ...
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
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) | 0,000 | 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 ».