Protein Abundance of Drug Metabolizing Enzymes in Human Hepatitis C Livers

Author:

Drozdzik Marek1ORCID,Lapczuk-Romanska Joanna1ORCID,Wenzel Christoph2ORCID,Skalski Lukasz1,Szeląg-Pieniek Sylwia1,Post Mariola3,Parus Arkadiusz4ORCID,Syczewska Marta5ORCID,Kurzawski Mateusz6,Oswald Stefan7ORCID

Affiliation:

1. Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland

2. Department of Pharmacology, Center of Drug Absorption and Transport, University Medicine Greifswald, 17489 Greifswald, Germany

3. Department of General and Transplantation Surgery, County Hospital, 71-455 Szczecin, Poland

4. Department of Mechatronics, West Pomeranian University of Technology, 70-310 Szczecin, Poland

5. Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, 71-455 Szczecin, Poland

6. Laboratory of Pharmacodynamics, Pomeranian Medical University, 71-899 Szczecin, Poland

7. Institute of Pharmacology and Toxicology, Rostock University Medical Center, 18057 Rostock, Germany

Abstract

Hepatic drug metabolizing enzymes (DMEs), whose activity may be affected by liver diseases, are major determinants of drug pharmacokinetics. Hepatitis C liver samples in different functional states, i.e., the Child–Pugh class A (n = 30), B (n = 21) and C (n = 7) were analyzed for protein abundances (LC-MS/MS) and mRNA levels (qRT-PCR) of 9 CYPs and 4 UGTs enzymes. The protein levels of CYP1A1, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 were not affected by the disease. In the Child–Pugh class A livers, a significant up-regulation of UGT1A1 (to 163% of the controls) was observed. The Child–Pugh class B was associated with down-regulation of the protein abundance of CYP2C19 (to 38% of the controls), CYP2E1 (to 54%), CYP3A4 (to 33%), UGT1A3 (to 69%), and UGT2B7 (to 56%). In the Child–Pugh class C livers, CYP1A2 was found to be reduced (to 52%). A significant trend in down-regulation of the protein abundance was documented for CYP1A2, CYP2C9, CYP3A4, CYP2E1, UGT2B7, and UGT2B15. The results of the study demonstrate that DMEs protein abundances in the liver are affected by hepatitis C virus infection and depend on the severity of the disease.

Funder

Minister of Science and Higher Education

National Science Centre, Cracow, Poland

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference56 articles.

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5. European Medicines Agency 2005 (2022, December 04). Guideline on the Evaluation of the Pharmacokinetics of Medicinal Products in Patients with Impaired Hepatic Function. February 2005 [Online]. Available online: https://www.ema.europa.eu/documents/scientific-guideline/guideline-evaluation-pharmacokinetics-medicinal-products-patients-impaired-hepatic-function_en.pdf.

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