Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites

A. L. Slitt, Nathan J Cherrington, J. M. Maher, Curtis D. Klaassen

Research output: Contribution to journalArticle

63 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1176-1186
Number of pages11
JournalDrug Metabolism and Disposition
Volume31
Issue number9
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

Fingerprint

Acetaminophen
Metabolites
Liver
Rats
Bile
Animals
Proteins
Blood
Urine
Protein Transport
Phenobarbital
multidrug resistance protein 3
acetaminophen glucuronide
Up-Regulation
Plasmas
Messenger RNA
stilbene oxide
Enzymes
Pharmaceutical Preparations
allyl sulfide

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites. / Slitt, A. L.; Cherrington, Nathan J; Maher, J. M.; Klaassen, Curtis D.

In: Drug Metabolism and Disposition, Vol. 31, No. 9, 01.09.2003, p. 1176-1186.

Research output: Contribution to journalArticle

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