dc.contributor.author |
Burns, Kathryn |
en |
dc.contributor.author |
Shepherd, Phillip |
en |
dc.contributor.author |
Finlay, Graeme |
en |
dc.contributor.author |
Tingle, Malcolm |
en |
dc.contributor.author |
Helsby, Nuala |
en |
dc.date.accessioned |
2018-10-18T01:37:09Z |
en |
dc.date.issued |
2018-08 |
en |
dc.identifier.issn |
0049-8254 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/42806 |
en |
dc.description.abstract |
1. Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2'-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19 and five of its known transcription factors (TF) has been assessed in cell lines derived from neoplastic liver and intestine. 2. CYP2C19 mRNA was substantially up-regulated (>18-fold) after treatment with 5azaDC despite the fact that the two intronic CpG islands in this gene remained substantially methylated (>50%). The TF NR1I3 was also consistently up-regulated after treatment with 5azaDC. NR1I3 lacks CpG islands in the proximal promoter region and is therefore not likely to be directly regulated by DNA methylation. Therefore, it appears that 5azaDC treatment affects an unidentified upstream regulator of both CYP2C19 and/or NR1I3. This is supported by the fact that the relationships between TF for CYP2C19 and the expression of this target gene in human liver samples only accounted for ∼70% of the variability of CYP2C19 mRNA levels. These data suggest that an yet un-identified 'master regulator' of CYP2C19 transcription could itself be a target of epigenetic control. |
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dc.format.medium |
Print-Electronic |
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dc.language |
eng |
en |
dc.relation.ispartofseries |
Xenobiotica; the fate of foreign compounds in biological systems |
en |
dc.rights |
Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. |
en |
dc.rights.uri |
https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm |
en |
dc.subject |
Humans |
en |
dc.subject |
Azacitidine |
en |
dc.subject |
Receptors, Cytoplasmic and Nuclear |
en |
dc.subject |
DNA Methylation |
en |
dc.subject |
Transcription, Genetic |
en |
dc.subject |
Gene Expression Regulation, Enzymologic |
en |
dc.subject |
Response Elements |
en |
dc.subject |
Hep G2 Cells |
en |
dc.subject |
Cytochrome P-450 CYP2C19 |
en |
dc.title |
Indirect regulation of CYP2C19 gene expression via DNA methylation. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1080/00498254.2017.1372648 |
en |
pubs.issue |
8 |
en |
pubs.begin-page |
781 |
en |
pubs.volume |
48 |
en |
dc.rights.holder |
Copyright: The author |
en |
dc.identifier.pmid |
28840784 |
en |
pubs.end-page |
792 |
en |
pubs.publication-status |
Published |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Journal Article |
en |
pubs.elements-id |
656792 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Molecular Medicine |
en |
pubs.org-id |
Pharmacology |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
dc.identifier.eissn |
1366-5928 |
en |
pubs.record-created-at-source-date |
2017-08-26 |
en |
pubs.dimensions-id |
28840784 |
en |