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Research ArticleArticle

INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 IN RAT LIVER IS ASSOCIATED WITH ALTERED VECTORIAL EXCRETION OF ACETAMINOPHEN METABOLITES

A. L. Slitt, N. J. Cherrington, J. M. Maher and C. D. Klaassen
Drug Metabolism and Disposition September 2003, 31 (9) 1176-1186; DOI: https://doi.org/10.1124/dmd.31.9.1176
A. L. Slitt
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N. J. Cherrington
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J. M. Maher
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C. D. Klaassen
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Abstract

Treatment with the microsomal enzyme inducer trans-stilbene oxide (TSO) can decrease biliary excretion of acetaminophen-glucuronide (AA-GLUC) and increase efflux of AA-GLUC into blood. The hepatic canalicular multidrug resistance protein (Mrp) 2 and sinusoidal protein Mrp3 transport AA-GLUC conjugates into bile and blood, respectively. Thus, TSO-induced alterations in the vectorial excretion of AA-GLUC may occur via increased hepatic Mrp3 levels. The goal of this study was to determine whether TSO, diallyl sulfide (DAS), and oltipraz (OLT) treatments can up-regulate Mrp3 protein expression, and whether treatment with DAS and OLT can correspondingly increase hepatovascular efflux of AA metabolites. Rats were administered phenobarbital, TSO, DAS, OLT, or vehicle for 4 days. Interestingly, all of the chemicals increased the plasma concentration and urinary excretion of AA-GLUC and decreased its biliary excretion. In control animals, approximately 77% and 23% of AA-GLUC was excreted into bile or urine, respectively, whereas with inducer-pretreated animals, <32% of AA-GLUC was excreted into bile and >68% was excreted into urine. Correspondingly, all of the compounds increased hepatic Mrp3 mRNA levels by 13- to 37-fold and protein levels by 2- to 6-fold, respectively. In conclusion, these studies correlate increased Mrp3 protein levels in liver with increased hepatovascular excretion of AA-GLUC and suggest that induction of Mrp3 affects the route of drug excretion.

Footnotes

  • ↵2 Abbreviations used are: AA, acetaminophen; AA-GLUC, acetaminophen-glucuronide; AA-SULF, acetaminophen-sulfate; AA-GSH, acetaminophen-glutathione; AA-NAC, acetaminophen-N-acetyl-l-cysteine (mercapturate); PB, phenobarbital; TSO, trans-stilbene oxide; Mrp2, multiple drug resistance protein 2; Mrp3, multiple drug resistance protein 3; EHBR, Eisai hyperbilirubinemic rat; GY/TR-, Groningen-Yellow transport-deficient rat; DAS, diallyl sulfide; OLT, oltipraz; HPLC, high performance liquid chromatography; RLU, relative light unit(s); PAGE, polyacrylamide; TBS, Tris-buffered saline; TBS-T, TBS/Tween 20; FITC, fluorescein isothiocyanate; bDNA, branched DNA signal amplification; GST, glutathione S-transferase; Oatp, organic anion polypeptide transport protein; CAR, constitutive androstane receptor; nrf2, nuclear factor-E2-related factor 2.

  • Financial support for this research was provided by National Institutes Health Grants ES-09716, ES-07079, and ES-11239. A.L.S. was supported National Institutes of Health Grant ES-011239-01. This work was presented in at the annual Society of Toxicology meeting, 2002 March 18–21.

  • ↵1 Present address: Department of Pharmacology and Toxicology, PO Box 210207, 1703 E. Mabel St., Tucson, AZ 85721-0207.

    • Received November 14, 2002.
    • Accepted June 6, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (9)
Drug Metabolism and Disposition
Vol. 31, Issue 9
1 Sep 2003
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Research ArticleArticle

INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 IN RAT LIVER IS ASSOCIATED WITH ALTERED VECTORIAL EXCRETION OF ACETAMINOPHEN METABOLITES

A. L. Slitt, N. J. Cherrington, J. M. Maher and C. D. Klaassen
Drug Metabolism and Disposition September 1, 2003, 31 (9) 1176-1186; DOI: https://doi.org/10.1124/dmd.31.9.1176

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Research ArticleArticle

INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 IN RAT LIVER IS ASSOCIATED WITH ALTERED VECTORIAL EXCRETION OF ACETAMINOPHEN METABOLITES

A. L. Slitt, N. J. Cherrington, J. M. Maher and C. D. Klaassen
Drug Metabolism and Disposition September 1, 2003, 31 (9) 1176-1186; DOI: https://doi.org/10.1124/dmd.31.9.1176
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