Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Combination treatment with 6-mercaptopurine and allopurinol in HepG2 and HEK293 cells - Effects on gene expression levels and thiopurine metabolism
Regional Jonköping County, Sweden; Karolinska Institute, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Regional Jonköping County, Sweden.
2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 3, e0173825Article in journal (Refereed) Published
Abstract [en]

Combination treatment with low-dose thiopurine and allopurinol (AP) has successfully been used in patients with inflammatory bowel disease with a so called skewed thiopurine metabolite profile. In red blood cells in vivo, it reduces the concentration of methylated metabolites and increases the concentration of the phosphorylated ones, which is associated with improved therapeutic efficacy. This study aimed to investigate the largely unknown mechanism of AP on thiopurine metabolism in cells with an active thiopurine metabolic pathway using HepG2 and HEK293 cells. Cells were treated with 6-mercaptopurine (6MP) and AP or its metabolite oxypurinol. The expression of genes known to be associated with thiopurine metabolism, and the concentration of thiopurine metabolites were analyzed. Gene expression levels were only affected by AP in the presence of 6MP. The addition of AP to 6MP affected the expression of in total 19 genes in the two cell lines. In both cell lines the expression of the transporter SLC29A2 was reduced by the combined treatment. Six regulated genes in HepG2 cells and 8 regulated genes in HEK293 cells were connected to networks with 18 and 35 genes, respectively, present at known susceptibility loci for inflammatory bowel disease, when analyzed using a protein-protein interaction database. The genes identified as regulated as well as the disease associated interacting genes represent new candidates for further investigation in the context of combination therapy with thiopurines and AP. However, no differences in absolute metabolite concentrations were observed between 6MP+AP or 6MP +oxypurinol vs. 6MP alone in either of the two cell lines. In conclusion; the effect of AP on=gene expression levels requires the presence of 6MP, at least in vitro. Previously described AP-effects on metabolite concentrations observed in red blood cells in vivo could not be reproduced in our cell lines in vitro. APs effects in relation to thiopurine metabolism are complex. The network-identified susceptibility genes represented biological processes mainly associated with purine nucleotide biosynthetic processes, lymphocyte proliferation, NF-KB activation, JAK-STAT signaling, and apoptotic signaling at oxidative stress.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2017. Vol. 12, no 3, e0173825
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-136041DOI: 10.1371/journal.pone.0173825ISI: 000396087900038PubMedID: 28278299OAI: oai:DiVA.org:liu-136041DiVA: diva2:1084888
Note

Funding Agencies|Futurum - the academy for health and care; Region Jonkoping County; Magtarm-fonden; Bengt-Ihre fonden; Karolinska Institutets forskningsfonder, Sweden

Available from: 2017-03-27 Created: 2017-03-27 Last updated: 2017-04-14

Open Access in DiVA

fulltext(1476 kB)11 downloads
File information
File name FULLTEXT01.pdfFile size 1476 kBChecksum SHA-512
1d024052b6602c8101e95e3f74bcb2e84513542f28651a68d29028fe045ad1bab98f42f939d393fbde47330ee899201f75528757270d145d9a2067cc6fba61a5
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Vikingsson, SvanteSöderman, Jan
By organisation
Division of Drug ResearchFaculty of Medicine and Health SciencesDivision of Cell Biology
In the same journal
PLoS ONE
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 11 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 60 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf