Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC-MS/MS Proteomics

• Published in: Drug metabolism and disposition 2018-02, Vol.46 (2), p.189-196
• Main Authors: Billington, Sarah, Ray, Adrian S., Salphati, Laurent, Xiao, Guangqing, Chu, Xiaoyan, Humphreys, W. Griffith, Liao, Mingxiang, Lee, Caroline A., Mathias, Anita, Hop, Cornelis E.C.A., Rowbottom, Christopher, Evers, Raymond, Lai, Yurong, Kelly, Edward J., Prasad, Bhagwat, Unadkat, Jashvant D.
• Format: Article
• Language: English
• Subjects: ATP-Binding Cassette Transporters - metabolism; Bile; Carcinoma, Hepatocellular - metabolism; Chromatography, Liquid - methods; Chronic infection; Female; Hepatitis; Hepatitis C; Hepatitis C, Chronic - metabolism; Hepatocellular carcinoma; Humans; Interferon; Liver; Liver - metabolism; Liver cancer; Liver Neoplasms - metabolism; Male; Membrane proteins; Middle Aged; Multidrug Resistance-Associated Proteins - metabolism; Organic Anion Transporters - metabolism; Patients; Proteomics; Proteomics - methods; Tandem Mass Spectrometry - methods; Tissues
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.117.077289

Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, n = 8) and adjacent noncancerous (NC, n = 33) liver tissues obtained from patients with chronic hepatitis C with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from noninfected, noncirrhotic (control, n = 36) and HCV-cirrhotic (n = 30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers. In comparison with control livers, with the exception of NTCP, MRP2, and MATE1, transporter expression decreased in NC (38%–76%) and C (56%–96%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP expression increased (113%), MATE1 expression decreased (58%), and MRP2 expression was unchanged relative to control livers. In C HCV-HCC tissues, NTCP and MRP2 expression decreased (63%, 56%) and MATE1 expression was unchanged relative to control livers. Compared with HCV-cirrhotic livers, aside from NTCP, OCT1, BSEP, and MRP2, transporter expression decreased in NC (41%–71%) and C (54%–89%) HCV-HCC tissues. In NC HCV-HCC tissues, NTCP and MRP2 expression increased (362%, 142%), whereas OCT1 and BSEP expression was unchanged. In C HCV-HCC tissues, OCT1 and BSEP expression decreased (90%, 80%) relative to HCV-cirrhotic livers, whereas NTCP and MRP2 expression was unchanged. Expression of OATP2B1, BSEP, MRP2, and MRP3 decreased (56%–72%) in C HCV-HCC tissues in comparison with matched NC tissues (n = 8), but the expression of other transporters was unchanged. These data will be helpful in the future to predict transporter-mediated hepatocellular drug concentrations in patients with HCV-HCC.