通过 LC-MS/MS 蛋白质组学定量分析患有肝细胞癌和慢性丙型肝炎感染的供体的非癌性和癌性肝组织中的转运蛋白表达。
Transporter Expression in Noncancerous and Cancerous Liver Tissue from Donors with Hepatocellular Carcinoma and Chronic Hepatitis C Infection Quantified by LC-MS/MS Proteomics.
机构信息
Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.).
Department of Pharmaceutics, University of Washington, Seattle, Washington (S.B., E.J.K., B.P., J.D.U.); Departments of Clinical Research, Clinical Pharmacology, and Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California (A.S.R., A.M., Y.L.); Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California (L.S., C.E.C.A.H.); DMPK, Biogen Idec, Cambridge, Massachusetts (G.X., C.R.); Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey (X.C., R.E.); Bristol-Myers Squibb Company, Princeton, New Jersey (W.G.H.); Takeda Pharmaceuticals International Co., Cambridge, Massachusetts (M.L.); and Translational Sciences, Ardea Biosciences, Inc., San Diego, California (C.A.L.)
出版信息
Drug Metab Dispos. 2018 Feb;46(2):189-196. doi: 10.1124/dmd.117.077289. Epub 2017 Nov 14.
Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs, and P-gp) in cancerous (C, = 8) and adjacent noncancerous (NC, = 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, = 36) and HCV-cirrhotic ( = 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 ( = 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.
通过 LC-MS/MS 蛋白质组学定量分析了来自慢性丙型肝炎合并肝细胞癌（HCV-HCC）患者的癌性（C，n=8）和相邻非癌性（NC，n=33）肝组织中主要肝胆药物转运体（NTCP、OATPs、OCT1、BSEP、BCRP、MATE1、MRPs 和 P-糖蛋白）的蛋白表达。在此，我们将我们的结果与我们之前来自未感染、非肝硬化（对照，n=36）和 HCV 肝硬化（n=30）肝脏的研究数据进行了比较。与对照肝脏相比，NC 和 C HCV-HCC 组织中膜蛋白的含量分别减少了（31%，67%）。与对照肝脏相比，除了 NTCP、MRP2 和 MATE1，NC（38%-76%）和 C（56%-96%）HCV-HCC 组织中转运体的表达均降低。在 NC HCV-HCC 组织中，NTCP 表达增加（113%），MATE1 表达降低（58%），MRP2 表达与对照肝脏相比无变化。在 C HCV-HCC 组织中，NTCP 和 MRP2 表达降低（63%，56%），MATE1 表达与对照肝脏相比无变化。与 HCV 肝硬化肝脏相比，除了 NTCP、OCT1、BSEP 和 MRP2，NC（41%-71%）和 C（54%-89%）HCV-HCC 组织中转运体的表达均降低。在 NC HCV-HCC 组织中，NTCP 和 MRP2 表达增加（362%，142%），而 OCT1 和 BSEP 表达无变化。在 C HCV-HCC 组织中，OCT1 和 BSEP 表达降低（90%，80%）与 HCV 肝硬化肝脏相比，而 NTCP 和 MRP2 表达无变化。与匹配的 NC 组织（n=8）相比，C HCV-HCC 组织中 OATP2B1、BSEP、MRP2 和 MRP3 的表达降低（56%-72%），但其他转运体的表达无变化。这些数据将有助于预测 HCV-HCC 患者肝细胞药物浓度的转运体介导作用。
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