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

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Abstract

Purpose

The present study examined the underlying mechanism by which 4-hydroxyacetophenone (4-HA), a bioactive compound found in several medicinal herbs, exerts its potent stimulatory effects on hepatic bile secretion.

Methods

Bile flow, and biliary excretion of 4-HA, its metabolites, and inorganic electrolytes was examined in both normal Wistar rats and in TR- Wistar rats that have a congenital defect in the multidrug resistance-associated protein-2, Mrp2/Abcc2. The effects of 4-HA were also examined in animals treated with buthionine sulfoximine to decrease hepatic glutathione (GSH) levels.

Results

In normal rats, 4-HA dramatically increased bile flow rate, whereas it failed to exert a choleretic effect in TR- rats. This choleresis was not explained by increased biliary output of Na+, K+, Cl− or HCO3 −, or by increased biliary GSH excretion. Depletion of hepatic GSH with buthionine sulfoximine had no effect on the 4-HA-induced choleresis. HPLC analysis revealed that a single major compound was present in bile, namely.4-hydroxyacetophenone-4-O-β-glucuronide, and that the parent compound was not detected in bile. Biliary excretion of the glucuronide was directly correlated with the increases in bile flow. In contrast to normal rats, this 4-HA metabolite was not present in bile of TR− rats.

Conclusions

These results demonstrate that the major biliary metabolite of 4-HA in rats is the 4-O-β-glucuronide, a compound that is secreted into bile at high concentrations, and may thus account in large part for the choleretic effects of 4-HA. Transport of this metabolite across the canalicular membrane into bile requires expression of the Mrp2 transport protein.

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Abbreviations

BADF:

bile acid dependent flow

BAIF:

bile acid independent flow

BSO:

buthionine sulfoximine

GSH:

reduced glutathione

Mrp2:

multidrug resistance-associated protein-2

4-HA:

4-hydroxyacetophenone

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Acknowledgments

We thank Mr. Sirichai Kositarat (Central Instrument Facility, Faculty of Science, Mahidol University) for his technical assistance with HPLC analysis of 4-hydroxyacetophenone-4-O-β-glucuronide in bile samples of normal Wistar and TR− rats.

This study was supported by grants from the Royal Golden Jubilee program (to CM), the Thailand Research Fund, a research team strengthening grant from BIOTEC, and grants DK48823 and ES01247 from the USA National Institutes of Health (to NB).

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Authors and Affiliations

  1. Department of Physiology, Faculty of Science, Mahidol University, Rama 6 Rd, Bangkok, 10400, Thailand

    Chitrawina Mahagita, Khwanchit Tanphichai & Pawinee Piyachaturawat

  2. Department of Environmental Medicine, University of Rochester School of Medicine, Rochester,, NY, 14642, USA

    Chitrawina Mahagita & Nazzareno Ballatori

  3. Department of Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok, 10240, Thailand

    Apichart Suksamrarn

Authors
  1. Chitrawina Mahagita
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  2. Khwanchit Tanphichai
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  3. Apichart Suksamrarn
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  4. Nazzareno Ballatori
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  5. Pawinee Piyachaturawat
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Correspondence to Pawinee Piyachaturawat.

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Mahagita, C., Tanphichai, K., Suksamrarn, A. et al. 4-Hydroxyacetophenone-Induced Choleresis in Rats is Mediated by the Mrp2-Dependent Biliary Secretion of Its Glucuronide Conjugate. Pharm Res 23, 2603–2610 (2006). https://doi.org/10.1007/s11095-006-9097-z

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  • DOI: https://doi.org/10.1007/s11095-006-9097-z

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