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Research ArticleArticle

Uptake and Glutathione Conjugation of Ethacrynic Acid and Efflux of the Glutathione Adduct by Periportal and Perivenous Rat Hepatocytes

Rommel G. Tirona, Eugene Tan, Galina Meier and K. Sandy Pang
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1210-1219;
Rommel G. Tirona
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Eugene Tan
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Galina Meier
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K. Sandy Pang
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Abstract

We assessed the impact of zonal factors on the hepatic reduced glutathione (GSH) conjugation of ethacrynic acid (EA). Uptake of EA by enriched periportal (PP) and perivenous (PV) rat hepatocytes was characterized by both saturable (Vmaxuptake = 3.4 ± 1.7 and 3.2 ± 0.8 nmol/min/mg protein andKmuptake = 51 ± 13 and 44 ± 15 μM) and nonsaturable (12 ± 5 and 12 ± 3 μl/min/mg protein) components. Values for the overall GSH conjugation rates of EA (200 μM) were similar among the zonal hepatocytes and resembled those for the influx transport rates. In the absence of the hepatocyte membrane, GSH conjugation in PV and PP hepatocyte cytosol was similar, but a higher perivenous GSH conjugation activity toward EA (PV/PP of 2.4) that mirrored the higher PV/PP ratios of immunodetectable GSTs Ya (1.7) and Yb2 (2.5) was found in cell lysates obtained by the dual-digitonin-pulse perfusion technique. The GSH conjugation rates in the subcellular fragments were, however, much greater than those observed for intact hepatocytes. Efflux rates of the glutathione conjugate EA-SG from zonal hepatocytes were similar, as were levels of the immunodetectable multidrug-resistance protein 2/canalicular multispecific organic anion transporter (Mrp2/cMoat) in the 100,000 g pellets. The composite results suggest that the GSTs responsible for EA metabolism are more abundant in the PV region, albeit that the gradient of enzymatic activities is shallow. Despite the existence of zonal metabolic activity, the overall GSH conjugation rate of EA is homogeneous among cells because the reaction is rate limited by uptake, which occurs evenly. Results on EA-SG efflux suggest the acinar homogeneity in Mrp2/cMoat function for canalicular transport.

Footnotes

  • Send reprint requests to: Dr. K. Sandy Pang, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2. E-mail: pang{at}phm.utoronto.ca

  • ↵1 This work was supported by the Medical Research Council of Canada (Grants MA9104 and MT15657). R.G.T. was supported by fellowships from Merck-Frosst Canada, the Pharmaceutical Manufacturers Association of Canada–Health Research Foundation and MRC, and the University of Toronto Open Fellowship. This work was presented in part at the Annual Meeting of the American Association for the Study of Liver Diseases, 1998, Chicago, IL.

  • Received for publication June 11, 1999.

  • Abbreviations:
    GSH
    reduced glutathione
    GSSG
    oxidized glutathione
    EA
    ethacrynic acid
    EA-SG
    ethacrynic acid-glutathione conjugate
    CDNB
    1-chloro-2,4-dinitrobenzene
    PP
    periportal
    PV
    perivenous
    ALT
    alanine aminotransferase
    GS
    glutamine synthetase
    CYP
    cytochrome P-450
    Mrp2
    rat multidrug resistance protein 2
    MRP2
    human multidrug resistance protein 2
    cMoat
    rat canalicular multispecific organic anion transporter
    GST
    glutathioneS-transferase
    • Accepted September 2, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Uptake and Glutathione Conjugation of Ethacrynic Acid and Efflux of the Glutathione Adduct by Periportal and Perivenous Rat Hepatocytes

Rommel G. Tirona, Eugene Tan, Galina Meier and K. Sandy Pang
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1210-1219;

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Research ArticleArticle

Uptake and Glutathione Conjugation of Ethacrynic Acid and Efflux of the Glutathione Adduct by Periportal and Perivenous Rat Hepatocytes

Rommel G. Tirona, Eugene Tan, Galina Meier and K. Sandy Pang
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1210-1219;
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