Protein Abundance of Drug Transporters in Human Hepatitis C Livers

Abstract

Transmembrane drug transport in hepatocytes is one of the major determinants of drug pharmacokinetics. In the present study, ABC transporters (P-gp, MRP1, MRP2, MRP3, MRP4, BCRP, and BSEP) and SLC transporters (MCT1, NTCP, OAT2, OATP1B1, OATP1B3, OATP2B1, OCT1, and OCT3) were quantified for protein abundance (LC-MS/MS) and mRNA levels (qRT-PCR) in hepatitis C virus (HCV)-infected liver samples from the Child–Pugh class A (n = 30), B (n = 21), and C (n = 7) patients. Protein levels of BSEP, MRP3, MCT1, OAT2, OATP1B3, and OCT3 were not significantly affected by HCV infection. P-gp, MRP1, BCRP, and OATP1B3 protein abundances were upregulated, whereas those of MRP2, MRP4, NTCP, OATP2B1, and OCT1 were downregulated in all HCV samples. The observed changes started to be seen in the Child–Pugh class A livers, i.e., upregulation of P-gp and MRP1 and downregulation of MRP2, MRP4, BCRP, and OATP1B3. In the case of NTCP, OATP2B1, and OCT1, a decrease in the protein levels was observed in the class B livers. In the class C livers, no other changes were noted than those in the class A and B patients. The results of the study demonstrate that drug transporter protein abundances are affected by the functional state of the liver in hepatitis C patients.

Effect of Hepatic Impairment on OATP1B Activity: Quantitative Pharmacokinetic Analysis of Endogenous Biomarker and Substrate Drugs

“…(2022) with larger sample size of HCV livers demonstrated no statistically significant difference between healthy and Child‐Pugh categories for OATP1B1 and OATP1B3 expression. In addition to methodological differences in sample handling and quantitative proteomic analysis, challenges with samples harvesting in progressive liver disease were suggested to contribute to such a discrepancy 39 . Overall, data are limiting to implement protein abundance differences in the virtual populations to model disease‐induced changes in transport activity.…”

Effect of Chronic Hepatitis C on the Activity of the Membrane Transporters P‐gp and OATP1B1/BCRP on Patients With Different Stages of Hepatic Fibrosis

“…However, mRNA levels of MDR1 were decreased in a dose-dependent manner when human hepatoma HepG2 cells were exposed to cytokines TNF-α and IL-1β. 14 Previous studies of protein abundance of hepatic transporters in liver tissues of patients with chronic hepatitis C associated with cirrhosis have reported increased, 20 no change in 19 or decreased 17 P-gp expression. It is noteworthy, however, that all these previous studies only account for hepatic P-gp.…”

“…23 Rosuvastatin is a hydrophilic statin with low oral bioavailability (≈ 20%) limited by BCRP expressed on the apical membrane of enterocytes, extensively distributed to the liver through active transport primarily mediated by OATP1B1, limited metabolism to the inactive metabolite rosuvastatin lactone and to the active metabolite N-desmethylrosuvastatin (dependent on CYP2C9), and it is primarily eliminated into the feces (>90%) as the unchanged drug, mediated predominantly by BCRP. 24,25 Previous in vitro studies [13][14][15][16][17][18][19][20] report the relationship between HCV replication and its effect on membrane transporter activity and emphasize the importance of confirming this result in vivo. Chronic hepatitis C, the progression of hepatic fibrosis, and the presence of cirrhosis may be followed by the alteration in the panel of pro-inflammatory cytokines, which among other mechanisms, may result in the inhibition or induction of the expression of membrane transporters involved in the absorption, distribution, and elimination of several drugs used in the clinic.…”

Overcoming Biological Barriers: Importance of Membrane Transporters in Homeostasis, Disease and Disease Treatment

“…They showed that increased cholesterol levels, which are observed in NAFLD and in nonalcoholic steatohepatitis (NASH) can impair the function of NTCP and OCT1, two important hepatic transporters, and may therefore change drug disposition in the liver. The paper “Protein Abundance of Drug Transporters in Human Hepatitis C Livers“ by Droździk et al [ 17 ] describes the measurement of abundance of several transporters by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in human hepatitis C virus (HCV)-infected liver samples. The abundances of P-gp, multiple drug-resistance-associated protein (MRP) 1 (MRP1), breast cancer resistance protein, and organic anion transporting polypeptide 1 (OATP1)-B3 (OATP1B3) protein were upregulated, whereas those of MRP2, MRP4, NTCP, OATP2B1, and OCT1 were downregulated in all HCV samples.…”