Abstract
BackgroundDrug metabolizing enzymes (DMEs) exhibit dramatic inter- and intra-individual variability in expression and activity. However, the mechanisms determining this variability have not been fully elucidated. The aim of this study was to evaluate the biological significance of DNA methylation in the regulation of DME genes by genome-wide integrative analysis.ResultsDNA methylation and mRNA expression profiles of human tissues and hepatoma cells were examined by microarrays. The data were combined with GEO datasets of liver tissues, and integrative analysis was performed on selected DME genes. Detailed DNA methylation statuses at individual CpG sites were evaluated by DNA methylation mapping. From analysis of 20 liver tissues, highly variable DNA methylation was observed in 37 DME genes, 7 of which showed significant inverse correlations between DNA methylation and mRNA expression. In hepatoma cells, treatment with a demethylating agent resulted in upregulation of 5 DME genes, which could be explained by DNA methylation status. Interestingly, some DMEs were suggested to act as tumor-suppressor or housekeeper based on their unique DNA methylation features. Moreover, tissue-specific and age-dependent expression of UDP-glucuronosyltransferase 1A splicing variants was associated with DNA methylation status of individual first exons.ConclusionsSome DME genes were regulated by DNA methylation, potentially resulting in inter- and intra-individual differences in drug metabolism. Analysis of DNA methylation landscape facilitated elucidation of the role of DNA methylation in the regulation of DME genes, such as mediator of inter-individual variability, guide for correct alternative splicing, and potential tumor-suppressor or housekeeper.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0136-7) contains supplementary material, which is available to authorized users.
Highlights
Drug metabolizing enzymes (DMEs) exhibit dramatic inter- and intra-individual variability in expression and activity
In order to evaluate the significance of DNA methylation in the regulation of DME genes, we examined which DME genes were regulated by DNA methylation in normal liver tissues and hepatoma cells, whether the tissue-specific and agedependent expression of UGT1A isoforms could be regulated by DNA methylation, and whether DNA methylation profiles could be used to elucidate the specific roles of DME genes
DNA methylation profiles of DME genes in human tissues We examined DNA methylation profiles of two adult liver tissues (NLA and NL2), fetal liver tissue (NLF), adult small intestinal tissue (NSI), and three hepatoma cell lines (HepG2, HuH7, and JHH1) by HumanMethylation450 Bead Chip
Summary
Drug metabolizing enzymes (DMEs) exhibit dramatic inter- and intra-individual variability in expression and activity. Inter-individual differences in responses to drug therapy vary widely. Such differences are due in part to variable pharmacokinetics, which can be explained by diversity in genes affecting drug absorption, distribution, metabolism, and excretion (ADME) [1]. Genetic polymorphisms in cytochrome P450 (CYP) genes, such as CYP2C9, CYP2C19, and CYP2D6, affect drug metabolizing activity and lead to different drug responses [2,3,4]. The tissue-specific and agedependent expressions of the UGT1A isoforms are important determinants of drug efficacy and adverse reactions, the regulatory mechanisms involved in UGT1A expression cannot be explained by genetic polymorphisms. The mechanisms underlying inter- and intraindividual differences in responses to drug therapy have not been fully elucidated
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