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.

Critical Issues and Optimized Practices in Quantification of Protein Abundance Level to Determine Interindividual Variability in DMET Proteins by LC‐MS/MS Proteomics

“…The enzyme activity or abundance of multiple hepatic DMEs is differentially regulated in diseased condition. For example, a significantly lower hepatic expression or activity of DMEs and transporters in patients with liver cirrhosis is reported as compared to the noncirrhotic subjects . Further, splice variants of DMET proteins such as CYP3A5 and CYP2C19 result in complete loss of activity, while a nonsynonymous single nucleotide polymorphism (SNP) of hepatic organic anion transporting polypeptide 1B1 (OATP1B1), c.463C>A, is associated with increased transporter function in human .…”

“…For example, since clinical trials are not routinely conducted during drug development on orphan populations such as children, DMET proteomics‐based PBPK models could help in making appropriate decisions when giving first‐dose of a drug to such populations based on studies in adult control population. It has been previously demonstrated that DMET proteins can be precisely quantified in human tissues and the data obtained can be used to predict the effect of genetic variation, age, and disease condition …”

Effect of Liver Disease on Hepatic Transporter Expression and Function

“…108,109 In the presence of HCV-induced cirrhosis, expression of NTCP, OATP1B3, and OCT1 are decreased compared to control samples using proteomic analysis. 110 …”

“…112 In HCV-induced cirrhosis, protein expression of BSEP, MRP2, and P-gp are downregulated whereas BCRP and MATE1 are unchanged. 110 To date, the clinical relevance of these findings in HCV-infected patients is unclear. The systemic clearance of nelfinavir, a P-gp substrate, was reduced in HIV/HCV-co-infected patients compared to HIV-infected patients without HCV.…”

The Non-Invasive Liver Biopsy : Determining Hepatic Function in Diffuse and Focal LiverDisease

“…An observation that agrees with this finding is that the rat homologue mrp2 is upregulated in dedicated cirrhotic rat model systems (136)(137)(138). In contrast, in humans Bonin et al did not find a significant difference in MRP2 expression (139), whereas Wang et al found some increased MRP2 expression in cirrhotic patients (140).…”