Transporter Expression in Liver Tissue from Subjects with Alcoholic or Hepatitis C Cirrhosis Quantified by Targeted Quantitative Proteomics.

Abstract

Although data are available on the change of expression/activity of drug-metabolizing enzymes in liver cirrhosis patients, corresponding data on transporter protein expression are not available. Therefore, using quantitative targeted proteomics, we compared our previous data on noncirrhotic control livers (n = 36) with the protein expression of major hepatobiliary transporters, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance-associated protein (MRP)2, MRP3, MRP4, sodium taurocholate-cotransporting polypeptide (NTCP), organic anion-transporting polypeptides (OATP)1B1, 1B3, 2B1, organic cation transporter 1 (OCT1), and P-glycoprotein (P-gp) in alcoholic (n = 27) and hepatitis C cirrhosis (n = 30) livers. Compared with control livers, the yield of membrane protein from alcoholic and hepatitis C cirrhosis livers was significantly reduced by 56 and 67%, respectively. The impact of liver cirrhosis on transporter protein expression was transporter-dependent. Generally, reduced protein expression (per gram of liver) was found in alcoholic cirrhosis livers versus control livers, with the exception that the expression of MRP3 was increased, whereas no change was observed for MATE1, MRP2, OATP2B1, and P-gp. In contrast, the impact of hepatitis C cirrhosis on protein expression of transporters (per gram of liver) was diverse, showing an increase (MATE1), decrease (BSEP, MRP2, NTCP, OATP1B3, OCT1, and P-gp), or no change (BCRP, MRP3, OATP1B1, and 2B1). The expression of hepatobiliary transporter protein differed in different diseases (alcoholic versus hepatitis C cirrhosis). Finally, incorporation of protein expression of OATP1B1 in alcoholic cirrhosis into the Simcyp physiologically based pharmacokinetics cirrhosis module improved prediction of the disposition of repaglinide in liver cirrhosis patients. These transporter expression data will be useful in the future to predict transporter-mediated drug disposition in liver cirrhosis patients.

• Authors: Li Wang, Carol Collins, Edward J Kelly, Xiaoyan Chu, Adrian S Ray, Laurent Salphati, Guangqing Xiao, Caroline Lee, Yurong Lai, Mingxiang Liao, Anita Mathias, Raymond Evers, William Humphreys, Cornelis E C A Hop, Sean C Kumer, Jashvant D Unadkat
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 44 Issue 11 Pg. 1752-1758 (11 2016) ISSN: 1521-009X [Electronic] United States
• PMID: 27543206 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• ABCC2 protein, human
• Membrane Proteins
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Proteome
• Ethanol

Topics

• Ethanol (metabolism)
• Female
• Hepatitis C (metabolism)
• Hepatocytes (metabolism)
• Humans
• Liver (metabolism)
• Liver Cirrhosis (metabolism)
• Male
• Membrane Proteins (metabolism)
• Membrane Transport Proteins (metabolism)
• Middle Aged
• Multidrug Resistance-Associated Protein 2
• Proteome (metabolism)
• Proteomics (methods)