4-Hydroxyacetophenone-Induced Choleresis in Rats is Mediated by the Mrp2-Dependent Biliary Secretion of Its Glucuronide Conjugate

Mahagita, Chitrawina; Tanphichai, Khwanchit; Suksamrarn, Apichart; Ballatori, Nazzareno; Piyachaturawat, Pawinee

doi:10.1007/s11095-006-9097-z

Cited by 6 publications

(4 citation statements)

References 19 publications

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“…Indeed, two glucuronide metabolites of THA have been identified (S. Khamdang, A. Suksamrarn, and P. Piyachaturawat, unpublished observation). This finding is consistent with an earlier report that the glucuronide conjugation of phloracetophenone is the major biliary metabolite (11,16). Mrp2, the multispecific resistance-associated protein 2, plays an important role in the biliary excretion of a number of endogenous and exogenous compounds including glucuronide, glutathione, and sulfates conjugates (7).…”

Section: Discussionsupporting

confidence: 93%

“…In our earlier study on the choleretic effect of 4-monohydroxyacetophenone (a THA analog), there was a clear parallel increase in bile flow and metabolites in bile. Moreover, 4-monohydroxyacetophenone failed to exert a choleretic effect in TR Ϫ rats where the excretion of metabolites was absent (16). By analogy, the metabolites of THA should also be excreted in bile and provide the osmotic force for stimulating bile flow.…”

Section: Discussionmentioning

confidence: 99%

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Phloracetophenone-induced choleresis in rats is mediated through Mrp2

Tradtrantip¹,

Piyachaturawat²,

Soroka³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Phloracetophenone-induced choleresis in rats is mediated through Mrp2

Tradtrantip¹,

Piyachaturawat²,

Soroka³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…We compared the results with other researchers, for example, 4-hydroxyacetophenone (4-HAP) is known as a bioactive compound found in several medicinal herbs, exerts a potent stimulatory effect on hepatic bile secretion [ 29 ]. This chemical inhibits the adhesion and migration of tumor cells in vitro and reduces metastatic burden in an in vivo liver metastasis model [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

Primary assessment of medicines for expected migrastatic potential with holographic incoherent quantitative phase imaging

Suranova¹,

Ďuriš²,

Netikova³

et al. 2023

Biomed. Opt. Express

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Solid tumor metastases cause most cancer-related deaths. The prevention of their occurrence misses suitable anti-metastases medicines newly labeled as migrastatics. The first indication of migrastatics potential is based on an inhibition of in vitro enhanced migration of tumor cell lines. Therefore, we decided to develop a rapid test for qualifying the expected migrastatic potential of some drugs for repurposing. The chosen Q-PHASE holographic microscope provides reliable multifield time-lapse recording and simultaneous analysis of the cell morphology, migration, and growth. The results of the pilot assessment of the migrastatic potential exerted by the chosen medicines on selected cell lines are presented.

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“…The MRP-dependent biliary secretion pathway is also affected by other choleretically active plant compounds. Using similar approaches and experimental animals which have a congenital defect in MRP2 transporter, independent research groups demonstrated that the choleretic action of 4-hydroxyacetophenone from Aster and Artemisia species [39] and phloracetophenone from Curcuma comosa [40] is also mediated via the MRP2 secretory pathway. Results of these and other studies [41,42] suggest that the osmotic effects and excretion of the biliary electrolytes play important roles in the MRP2-dependent choleresis and may attenuate the cholestatic effects of hepatotoxins undergoing biotransformation in the liver and excretion via the MRP transporter system.…”

Section: Bsep-and Mrp-dependent Choleresismentioning

confidence: 99%

Mechanisms of Action of Herbal Cholagogues

Spiridonov

2012

Medicinal Aromatic Plants

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4-Hydroxyacetophenone-Induced Choleresis in Rats is Mediated by the Mrp2-Dependent Biliary Secretion of Its Glucuronide Conjugate

Cited by 6 publications

References 19 publications

Phloracetophenone-induced choleresis in rats is mediated through Mrp2

Phloracetophenone-induced choleresis in rats is mediated through Mrp2

Primary assessment of medicines for expected migrastatic potential with holographic incoherent quantitative phase imaging

Mechanisms of Action of Herbal Cholagogues

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