Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine
Journal Title: The AAPS Journal - Year 2010, Vol 12, Issue 4
Abstract
The low bioavailability of genistein has impeded its development into a therapeutic agent. Our earlier studies indicate that glucuronidation is one of the major barriers to genistein oral bioavailability. This study will determine how sulfotransferases and efflux transporters affect its intestinal disposition. A rodent intestinal perfusion model and S9 fractions were used. Sulfate excretion rates were comparable to glucuronide excretion in mouse small intestine but significantly higher than glucuronide excretion in mouse colon, which is different from rat intestinal disposition but similar to disposition in Caco-2 cells. To define efflux transporter(s) involved in sulfate excretion, two organic anion inhibitors (estrone sulfate and dihydroepiandrosterone sulfate) or a multidrug resistance protein inhibitor (MK-571) were used but neither was able to decrease the excretion of genistein sulfates. In contrast, the excretion of genistein sulfate decreased substantially (>90%) in small intestine of breast cancer resistance protein (BCRP) knockout mice and became undetectable in colon of the knockout mice. The excretion rates of genistein glucuronide in the small intestine of BCRP knockout mice were also significant decreased (78%). This study shows clearly that BCRP facilitates the cellular genistein sulfate excretion by removing sulfates to prevent their backward hydrolysis and to limit substrate inhibition, indicating that BCRP plays a dominant role in genistein sulfate excretion and a significant role in genistein glucuronide excretion in the mouse intestine.
Authors and Affiliations
Wei Zhu, Haiyan Xu, Stephen W. J. Wang, Ming Hu
Keywords
Related Articles
- EP ID EP681416
- DOI 10.1208/s12248-010-9209-x
- Views 93
- Downloads 0
Development of a Population Pharmacokinetic Model for Taranabant, a Cannibinoid-1 Receptor Inverse Agonist
Taranabant is a cannabinoid-1 receptor inverse agonist developed for the treatment of obesity. A population model was constructed to facilitate the estimation of pharmacokinetic parameters and to identify the influence o...
New FDA Draft Guidance on Immunogenicity
A “Late Breaking” session was held on May 20 at the 2013 American Association of Pharmaceutical Scientists-National Biotech Conference (AAPS-NBC) to discuss the US Food and Drug Administration’s (...
R4 Regulator of G Protein Signaling (RGS) Proteins in Inflammation and Immunity
G protein-coupled receptors (GPCRs) have important functions in both innate and adaptive immunity, with the capacity to bridge interactions between the two arms of the host responses to pathogens through direct recogniti...
Brain tissue lipidomics: Direct probing using matrix-assisted laser desorption/ionization mass spectrometry
Lipidomics is the new frontier in biomolecular structural studies. Not only are lipids the main components in membranes that define the contours of the cell and its organelles, but they are also used for storage. Lipids...
AAPS–FIP Summary Workshop Report: Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications
The workshop “Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications” was held November 15–16, 2008 in Atlanta, Georgia, USA. This workshop provided an opportu...