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 94
- Downloads 0
Effect of Device Design and Formulation on the In Vitro Comparability for Multi-Unit Dose Dry Powder Inhalers
The online version of this article (doi:10.1208/s12248-015-9775-z) contains supplementary material, which is available to authorized users.
Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein
An hPepT1-GFP fusion construct was made to study drug inhibition of dipeptide uptake and apical, basolateral, or subcellular hPepT1 localization. The hPepT1 stop codon was mutated by polymerase chain reaction and was sub...
Preconditioning of Nonlinear Mixed Effects Models for Stabilisation of Variance-Covariance Matrix Computations
As the importance of pharmacometric analysis increases, more and more complex mathematical models are introduced and computational error resulting from computational instability starts to become a bottleneck in the analy...
Quantitative Prediction of Human Pharmacokinetics for mAbs Exhibiting Target-Mediated Disposition
The online version of this article (doi:10.1208/s12248-014-9690-8) contains supplementary material, which is available to authorized users.
Biodegradable Microparticles Loaded with Doxorubicin and CpG ODN for In Situ Immunization Against Cancer
In situ immunization is based on the concept that it is possible to break immune tolerance by inducing tumor cell death in situ in a manner that provides antigen-presenting cells such as dendritic cells (DCs) with a wide...