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Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for

Indrani Mukhopadhya1, Graeme I Murray2, Susan Berry1

  • 1School of Medicine & Dentistry, University of Aberdeen, Aberdeen, UK.

The Journal of Antimicrobial Chemotherapy
|October 31, 2015
PubMed
Abstract

Insights

This study mapped drug transporter mRNA in colorectal tissue and found Caco-2 cells are a good model. Antiretroviral drugs may cause interactions affecting HIV-1 microbicide distribution.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Gastroenterology

Background:

  • Rectal administration of microbicides is a key HIV-1 prevention strategy.
  • Understanding drug transporter expression in the colorectal epithelium is crucial for optimizing microbicide efficacy.
  • Antiretroviral (ARV) drugs can impact transporter function, potentially altering drug distribution.

Purpose of the Study:

  • To comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and cell lines.
  • To investigate how ARV drugs (tenofovir, darunavir, dapivirine) alter drug transporter gene expression in colorectal epithelium.
  • To inform the development of effective ARV-based microbicidal formulations for HIV-1 prevention.

Main Methods:

  • Quantitative real-time PCR was used to measure drug transporter mRNA expression in colorectal biopsies and cell lines.
  • Caco-2 cells and colorectal explants were exposed to ARVs to assess relative mRNA expression changes.
  • Data analysis involved Pearson's correlation, hierarchical clustering, and principal component analysis (PCA).

Main Results:

  • 58 of 84 transporters were detected in colorectal biopsies, with CNT2, P-glycoprotein (P-gp), and MRP3 showing highest expression.
  • Caco-2 cells were identified as the best surrogate system for colorectal tissue drug transporter gene expression.
  • ARV drug induction in Caco-2 cells indicated potential drug-drug interactions affecting microbicide distribution to target cells.

Conclusions:

  • Findings aid in optimizing rectal microbicide formulations for HIV-1 pre-exposure prophylaxis (PrEP).
  • Understanding transporter expression and ARV interactions is vital for successful microbicide development.
  • This research supports the potential of ARV-based microbicides for effective HIV-1 prevention.

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