Abstract
BackgroundHepatic 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.MethodsThe 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.ResultsSignificantly 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.ConclusionThe 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.
Highlights
Most of the drugs, as well as other xenobiotics, undergo biotransformation in the body, which has a significant impact on their pharmacokinetics and, in consequence, their actions and biological effects
Among investigated CYP450 enzymes, CYP2E1, CYP3A4, CYP2C9, CYP2C8, and CYP1A2 proteins were present at the highest concentrations in the liver tissues in both study groups, while CYP2D6, CYP2B6 and CYP2C19 protein content were distinctly lower
The rank order of particular CYPs proteins was different in the study groups [decreasing abundance order—mean values: CYP2E1 (43%) > CYP1A2 (15%) > CYP2C9 (13%) > CYP3A4 (12%) > CYP2C8 (9%) > CYP2D6 (3%) > CYP2B6 (3%) > CYP2C19 (1%) in donors, and CYP2C9 (32%) > CYP2E1 (25%) > CYP3A4 (13%) > CYP1A2 (12%) > CYP2C8 (8%) > CYP2D6 (4%) > CYP2C19 (2%) > CYP2B6 (2%) in metastatic patients], significant differences were only observed in case of CYP2C9 (U = 12, N1 = 11, N2 = 13, p = 0.0002) and CYP2D6 (U = 29, N1 = 11, N2 = 13, p = 0.0129)
Summary
As well as other xenobiotics, undergo biotransformation in the body, which has a significant impact on their pharmacokinetics and, in consequence, their actions and biological effects. There are two main sources of the control liver samples used as reference livers in published studies, i.e. donor livers [5, 7, 9] and non-tumorous tissue from metastatic livers [4, 8], and in some of the studies combined control groups were used [6] As it is not clear if liver DMEs are significantly affected by metastatic cancer or if they are altered in braindead organ donors (but both groups could represent the same functional liver state in a routine clinical screening), the present study aimed, for the first time, to characterize mRNA expression and protein abundance of the most pharmacologically relevant DMEs in the two most frequently used types of reference liver tissues. 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. Genotyping for common functional variants of CYP450 enzymes should be performed in all studies on drug-metabolizing enzymes
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