INVESTIGATION INTO THE EFFECTS OF TESTOSTERONE ON DRUG METABOLIZING ENZYMES IN HEPATIC AND INTESTINAL HUMAN CELL LINES
Notice bibliographique
Résumé
Introduction Testosterone is a well‐established probe substrate for assessing functional levels of cytochrome P450 (CYP) 3A4‐mediated metabolism. Parenteral testosterone replacement therapy is commonly prescribed for male hypogonadism, given the low oral bioavailability of oral testosterone. However, some investigators are exploring the oral delivery of testosterone or its esters using specialized formulations that might promote lymphatic intestinal absorption. Exogenous administration of hormones is known to down‐regulate endogenous production, which could lead to less than expected increases in exposure with repeated administration, but other factors such as self‐induction of metabolism could also contribute. There is little if any substantive information available that sheds light on whether or not testosterone has any inductive effects on CYP3A4 mediated metabolism, or on any other CYP isoforms. The intent of this study was to use intestinal and hepatic human cell lines to assess for possible induction of CYP3A4 and CYP1A1. Methods Human hepatic (HepG2) and colonic/intestinal (Lovo) cell lines were grown in 12 well plates and spiked with testosterone (300, 3000 or 30000 ng/dL once or twice daily for 3 days). Control cells were similarly treated with matching media minus testosterone. At the end of the 3 days of treatment, some cells were used to measure mRNA and protein for CYP1A1, CYP3A4, and multidrug resistance protein (MDR1). In addition, the effect of testosterone pretreatment on its own in vitro clearance, and CYP1A1–specific functional activity (using 7‐ethoxyin O‐deethylase activity) were also tested in the cell lines. Results Based on the mRNA and protein measures, there was no evidence of a testosterone‐related change in protein expression of the target genes or housekeeping genes. Functional studies indicated no change in CYP1A1 activity. Using a LC‐MS assay method, the cells lines displayed a rapid decrease in testosterone concentrations; it was established that there was no binding of testosterone to the plastic well plates used in the studies. HepG2 cells preexposed with 3000 ng/dL twice daily testosterone for 3 d had no associated changes in testosterone clearance after the testosterone preexposure phase. In the Lovo cells, testosterone pretreatment with 30000 ng/dL of testosterone was associated with an apparent inhibition in vitro of testosterone clearance. The testosterone concentrations exposed to intestinal cells were higher than liver cells because enterocyte exposure after oral administration would be expected to greatly exceed those in the liver. Conclusion There was no evidence for induction of testosterone metabolism in vitro using human liver and intestinal cell lines. The decrease in testosterone clearance in the intestinal cells after preexposure might have been due to accumulation of metabolites, with a pursuant competitive or noncompetitive inhibition of testosterone metabolism. Support or Funding Information Funding provided by TesoRx Pharma LLC This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| 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 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».