Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis

Mark J. Canet, Matthew D. Merrell, Rhiannon N. Hardwick, Amy M. Bataille, Sarah N. Campion, Daniel W. Ferreira, Stavra A. Xanthakos, Jose E. Manautou, Hassan H Hassan, Robert P. Erickson, Nathan J Cherrington

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

Original languageEnglish (US)
Pages (from-to)829-835
Number of pages7
JournalDrug Metabolism and Disposition
Volume43
Issue number6
DOIs
StatePublished - Jun 1 2015

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Acetaminophen
Pediatrics
Liver
Membrane Transport Proteins
Sulfur
Non-alcoholic Fatty Liver Disease
Tissue Distribution
Serum
Transcriptional Activation
Liver Diseases
Chronic Disease
High Pressure Liquid Chromatography
Urine
Pathology
acetaminophen glucuronide
acetaminophen sulfate ester

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. / Canet, Mark J.; Merrell, Matthew D.; Hardwick, Rhiannon N.; Bataille, Amy M.; Campion, Sarah N.; Ferreira, Daniel W.; Xanthakos, Stavra A.; Manautou, Jose E.; Hassan, Hassan H; Erickson, Robert P.; Cherrington, Nathan J.

In: Drug Metabolism and Disposition, Vol. 43, No. 6, 01.06.2015, p. 829-835.

Research output: Contribution to journalArticle

Canet, MJ, Merrell, MD, Hardwick, RN, Bataille, AM, Campion, SN, Ferreira, DW, Xanthakos, SA, Manautou, JE, Hassan, HH, Erickson, RP & Cherrington, NJ 2015, 'Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis', Drug Metabolism and Disposition, vol. 43, no. 6, pp. 829-835. https://doi.org/10.1124/dmd.114.062703
Canet, Mark J. ; Merrell, Matthew D. ; Hardwick, Rhiannon N. ; Bataille, Amy M. ; Campion, Sarah N. ; Ferreira, Daniel W. ; Xanthakos, Stavra A. ; Manautou, Jose E. ; Hassan, Hassan H ; Erickson, Robert P. ; Cherrington, Nathan J. / Altered regulation of hepatic efflux transporters disrupts acetaminophen disposition in pediatric nonalcoholic steatohepatitis. In: Drug Metabolism and Disposition. 2015 ; Vol. 43, No. 6. pp. 829-835.
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AU - Campion, Sarah N.

AU - Ferreira, Daniel W.

AU - Xanthakos, Stavra A.

AU - Manautou, Jose E.

AU - Hassan, Hassan H

AU - Erickson, Robert P.

AU - Cherrington, Nathan J

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AB - Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, representing a spectrum of liver pathologies that include simple hepatic steatosis and the more advanced nonalcoholic steatohepatitis (NASH). The current study was conducted to determine whether pediatric NASH also results in altered disposition of acetaminophen (APAP) and its two primary metabolites, APAP-sulfate and APAP-glucuronide. Pediatric patients with hepatic steatosis (n = 9) or NASH (n = 3) and healthy patients (n = 12) were recruited in a small pilot study design. All patients received a single 1000-mg dose of APAP. Blood and urine samples were collected at 1, 2, and 4 hours postdose, and APAP and APAP metabolites were determined by high-performance liquid chromatography. Moreover, human liver tissues from patients diagnosed with various stages of NAFLD were acquired from the Liver Tissue Cell Distribution System to investigate the regulation of the membrane transporters, multidrug resistance-associated protein 2 and 3 (MRP2 and MRP3, respectively). Patients with the more severe disease (i.e., NASH) had increased serum and urinary levels of APAP-glucuronide along with decreased serum levels of APAP-sulfate. Moreover, an induction of hepatic MRP3 and altered canalicular localization of the biliary efflux transporter, MRP2, describes the likely mechanism for the observed increase in plasma retention of APAP-glucuronide, whereas altered regulation of sulfur activation genes may explain decreased sulfonation activity in NASH. APAP-glucuronide and APAP-sulfate disposition is altered in NASH and is likely due to hepatic membrane transporter dysregulation as well as altered intracellular sulfur activation.

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