Submitted on December 20, 2006
Accepted on March 14, 2007
Phloracetophenone-Induced Choleresis in Rats is Mediated Through Mrp2
Lukmanee Tradtrantip1, Pawinee Piyachaturawat2, Carol Soroka3, Kathy Harry3, Albert Mennone3, Chitrawina Mahagita2, Nazzareno Ballatori4, and James L. Boyer5*
1 Liver Center, Yale University School of Medicine, New Haven, Connecticut, United States; Department of Physiology, Mahidol University, Bangkok, Thailand
2 Department of Physiology, Mahidol University, Bangkok, Thailand
3 Liver Center, Yale University School of Medicine, New Haven, Connecticut, United States
4 Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York, United States; United States
5 School of Medicine, Liver Center, Yale University, New Haven, Connecticut, United States
* To whom correspondence should be addressed. E-mail: james.boyer{at}yale.edu.
Phloracetophenone (2,4,6-trihydroxy acetophenone, 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. Step-wise 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 (BAIF). THA inhibited the biliary excretion of both sulfobromopthalein (BSP) and disulfobromopthalein (DBSP), typical multidrug resistance proteins-2 (Mrp2) 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-17
-D-glucuronide (E2-17G) 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.
