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

被引:53
作者
Billington, Sarah [1 ]
Ray, Adrian S. [2 ]
Salphati, Laurent [3 ]
Xiao, Guangqing [4 ]
Chu, Xiaoyan [5 ]
Humphreys, W. Griffith [6 ]
Liao, Mingxiang [7 ]
Lee, Caroline A. [8 ]
Mathias, Anita [2 ]
Hop, Cornelis E. C. A. [3 ]
Rowbottom, Christopher [4 ]
Evers, Raymond [5 ]
Lai, Yurong [2 ]
Kelly, Edward J. [1 ]
Prasad, Bhagwat [1 ]
Unadkat, Jashvant D. [1 ]
机构
[1] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA
[2] Gilead Sci Inc, Clin Pharmacol & Drug Metab & Pharmacokinet, Dept Clin Res, 353 Lakeside Dr, Foster City, CA 94404 USA
[3] Genentech Inc, Dept Drug Metab & Pharmacokinet, 460 Point San Bruno Blvd, San Francisco, CA 94080 USA
[4] Biogen Idec Inc, DMPK, Cambridge, MA USA
[5] Merck & Co Inc, Pharmacokinet Pharmacodynam & Drug Metab, Rahway, NJ USA
[6] Bristol Myers Squibb Co, Princeton, NJ USA
[7] Takeda Pharmaceut Int Co, Cambridge, MA USA
[8] Ardea Biosci Inc, Translat Sci, San Diego, CA USA
基金
美国国家卫生研究院;
关键词
MR IMAGING-CORRELATION; GD-EOB-DTPA; VIRUS-INFECTION; DRUG TRANSPORTERS; CONTRAST AGENT; INTERINDIVIDUAL VARIABILITY; QUANTITATIVE PROTEOMICS; RESISTANCE PROTEIN; DOWN-REGULATION; P-GLYCOPROTEIN;
D O I
10.1124/dmd.117.077289
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:189 / 196
页数:8
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