INVESTIGATION INTO THE EFFECTS OF TESTOSTERONE ON DRUG METABOLIZING ENZYMES IN HEPATIC AND INTESTINAL HUMAN CELL LINES
Bibliographic record
Abstract
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 .
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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 | 0.001 |
| 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) | 0.003 | 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".