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
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↵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.
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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.
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↵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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