Publication: Phloracetophenone-induced choleresis in rats is mediated through Mrp2
Issued Date
2007-07-01
Resource Type
ISSN
15221547
01931857
01931857
Other identifier(s)
2-s2.0-34547103287
Rights
Mahidol University
Rights Holder(s)
SCOPUS
Bibliographic Citation
American Journal of Physiology - Gastrointestinal and Liver Physiology. Vol.293, No.1 (2007)
Suggested Citation
Lukmanee Tradtrantip, Pawinee Piyachaturawat, Carol J. Soroka, Kathy Harry, Albert Mennone, Chitrawina Mahagita, Nazzareno Ballatori, James L. Boyer Phloracetophenone-induced choleresis in rats is mediated through Mrp2. American Journal of Physiology - Gastrointestinal and Liver Physiology. Vol.293, No.1 (2007). doi:10.1152/ajpgi.00578.2006 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/24175
Research Projects
Organizational Units
Authors
Journal Issue
Thesis
Title
Phloracetophenone-induced choleresis in rats is mediated through Mrp2
Other Contributor(s)
Abstract
Phloracetophenone (2,4,6-trihydroxyacetophenone, THA) is a potent choleretic in the bile fistula rat, although the mechanism is unknown. In the present study, we examined how THA enhances bile secretion. Stepwise infusions of THA (1-4 μmol/min) in the isolated perfused rat liver resulted in an immediate and dose-dependent increase in bile flow (BF), which reached saturation. The increase in BF was not associated with a change in the excretion of bile acids, suggesting that THA stimulated bile acid-independent bile flow. To further define the mechanism, the effect of THA on the excretion of sulfobromophthalein (BSP) and disulfobromophthalein (DBSP), typical multidrug resistance protein-2 (Mrp2) substrates was examined. THA inhibited the biliary excretion of both substrates. Because DBSP is excreted without conjugation to glutathione, in contrast to BSP, the findings suggest that THA might compete with DBSP and BSP metabolites at a common canalicular transport site, presumably Mrp2. THA infusions had no effect on the subcellular localization and distribution of either Mrp2 or the bile salt export pump (Bsep), nor the integrity of the tight junction. In contrast, the choleretic activity of THA was completely absent in the TR-rat, an animal model that lacks Mrp2, directly implicating this canalicular export pump as the mechanisms by which THA is excreted in bile. THA also partially reversed the cholestatic effects of estradiol-17β-D-glucuronide, a process also dependent on Mrp2. In conclusion, the choleretic activity of THA and its possible metabolites is dependent on Mrp2. THA appears to stimulate BF by its osmotic effects and may attenuate the cholestatic effects of hepatotoxins undergoing biotransformation and excretion via similar pathways. Copyright © 2007 the American Physiological Society.