Hepatic drug-metabolizing enzymes and drug transporters in Wilson's disease patients with liver failure
| Autor: | Stefan Oswald, Mariola Post, Marek Droździk, Mateusz Kurzawski, Joanna Łapczuk-Romańska, Sylwia Szeląg-Pieniek |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Adult Male Wilson’s disease Down-Regulation Protein abundance ATP-binding cassette transporter Pharmacology Article Liver disorder 03 medical and health sciences Young Adult 0302 clinical medicine Downregulation and upregulation Cytochrome P-450 Enzyme System Hepatolenticular Degeneration Drug transporters medicine Humans RNA Messenger CYP450 enzymes Aged chemistry.chemical_classification CYP3A4 business.industry Multidrug resistance-associated protein 2 Genetic disorder General Medicine Middle Aged medicine.disease Wilson's disease 030104 developmental biology Enzyme chemistry Liver Pharmaceutical Preparations 030220 oncology & carcinogenesis Female business Carrier Proteins Liver Failure |
| Zdroj: | Pharmacological Reports |
| ISSN: | 2299-5684 |
| Popis: | Background Wilson’s disease is a genetic disorder inherited in a recessive manner, caused by mutations in the copper-transporter ATP7B. Although it is a well-known disease, currently available treatments are far from satisfactory and their efficacy varies in individual patients. Due to the lack of information about drug-metabolizing enzymes and drug transporters profile in Wilson’s disease livers, we aimed to evaluate the mRNA expression and protein abundance of selected enzymes and drug transporters in this liver disorder. Methods We analyzed gene expression (qPCR) and protein abundance (LC–MS/MS) of 14 drug-metabolizing enzymes and 16 drug transporters in hepatic tissue from Wilson’s disease patients with liver failure (n = 7, Child–Pugh class B and C) and metastatic control livers (n = 20). Results In presented work, we demonstrated a downregulation of majority of CYP450 and UGT enzymes. Gene expression of analyzed enzymes ranged between 18 and 65% compared to control group and significantly lower protein content of CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP3A4 and CYP3A5 enzymes was observed in Wilson’s disease. Moreover, a general decrease in hepatocellular uptake carriers from SLC superfamily (significant at protein level for NTCP and OATP2B1) was observed. As for ABC transporters, the protein abundance of BSEP and MRP2 was significantly lower, while levels of P-gp and MRP4 transporters were significantly higher in Wilson’s disease. Conclusions Altered hepatic expression of drug‐metabolizing enzymes and drug transporters in Wilson’s disease patients with liver failure may result in changes of drug pharmacokinetics in that group of patients. |
| Databáze: | OpenAIRE |
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