Phloracetophenone-induced choleresis in rats is mediated through Mrp2.
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 micromol/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-17beta-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.
Tradtrantip
Lukmanee
L
Department of Physiology, Faculty of Science, Mahidol University, Bangkok, Thailand.
Piyachaturawat
Pawinee
P
Soroka
Carol J
CJ
Harry
Kathy
K
Mennone
Albert
A
Mahagita
Chitrawina
C
Ballatori
Nazzareno
N
Boyer
James L
JL
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013448:Sulfobromophthalein / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000098:Acetophenones; D013448:Sulfobromophthalein; C012479:dibromosulphthalein; C107067:2,4,6-trihydroxyacetophenone