The reference liver—CYP450 and UGT enzymes in healthy donor and metastatic livers: the impact of genotype

• Published in: Pharmacological reports 2022-02, Vol.74 (1), p.204-215
• Main Authors: Kurzawski, Mateusz, Szeląg-Pieniek, Sylwia, Łapczuk-Romańska, Joanna, Wrzesiński, Maciej, Oswald, Stefan, Droździk, Marek
• Format: Article
• Language: English
• Subjects: Cytochrome P-450 Enzyme System - genetics; Drug Safety and Pharmacovigilance; Gene Expression Profiling; Genotyping Techniques - methods; Humans; Inactivation, Metabolic - genetics; Liver - enzymology; Liver - pathology; Medicine; Neoplasm Metastasis - pathology; Pharmacogenomic Variants; Pharmacotherapy; Pharmacy; Tissue Donors; Xenobiotics - metabolism
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1007/s43440-021-00337-w

Background Hepatic enzymes involved in drug metabolism vary markedly in expression, abundance and activity, which affects individual susceptibility to drugs and toxicants. The present study aimed to compare mRNA expression and protein abundance of the most pharmacologically relevant drug-metabolizing enzymes in two main sources of the control liver samples that are used as the reference, i.e. organ donor livers and non-tumorous tissue from metastatic livers. An association analysis of the most common genetic variants with mRNA and protein levels was also performed. Methods The CYP450 and UGT enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, UGT1A1, UGT1A3, UGT2B7 and UGT2B15) were analyzed for mRNA (qPCR) and protein abundance (LC–MS/MS) in healthy donors ( n  = 11) and metastatic ( n  = 13) livers. Genotyping was performed by means of TaqMan assays and pyrosequencing. Results Significantly higher protein abundance in the metastatic livers was observed in case of CYP2C9, CYP2D6, and UGT2B7, and for UGT1A3 the difference was only significant at mRNA level. For all the enzymes except CYP2E1 some significant correlation between mRNA and protein content was observed, and for UGT1A1 an inverse correlation with age was noted. CYP2C19, CYP3A5 and CYP2D6 were significantly affected by genotype. Conclusion The selection of a control group for the study on drug-metabolizing enzymes (e.g. in pathological states) may possibly affect its conclusions on differences in mRNA and protein content. Genotyping for common functional variants of CYP450 enzymes should be performed in all studies on drug-metabolizing enzymes.