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Decrease in S-adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4
E H Stet1, R A De Abreu, J P Bökkerink
1Department of Pediatrics, St. Radboud University Hospital of Nijmegen, The Netherlands.
Abstract:
6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine anti-metabolites which are both metabolized to methylthio-IMP (Me-tIMP), a strong inhibitor of purine synthesis de novo. Me-MPR is converted directly into Me-tIMP by adenosine kinase. 6-MP is converted into tIMP, and thereafter it is methylated to Me-tIMP by thiopurine methyltransferase, an S-adenosylmethionine (S-Ado-Met)-dependent conversion. S-Ado-Met is formed from methionine and ATP by methionine adenosyltransferase, and is a universal methyl donor, involved in methylation of several macromolecules, e.g. DNA and RNA. Therefore, depletion of S-Ado-Met could result in an altered methylation state of these macromolecules, thereby affecting their functionality, leading to dysregulation of cellular processes and cytotoxicity. In this study the effects of 6-MP and Me-MPR on S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine and methionine concentrations are determined. Both drugs cause a decrease in intracellular S-Ado-Met concentrations and an increase in S-Ado-Hcy and methionine concentrations in Molt F4 human malignant lymphoblasts. The effects of both 6-MP and Me-MPR can be ascribed to a decreased conversion of methionine into S-Ado-Met, due to the ATP depletion induced by the inhibition of purine synthesis de novo by Me-tIMP. Both 6-MP and Me-MPR thus affect the methylation state of the cells, and this may result in dysregulation of cellular processes and may be an additional mechanism of cytotoxicity for 6-MP and Me-MPR.
Insights
6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) decrease S-adenosylmethionine (S-Ado-Met) levels by inhibiting purine synthesis. This impacts cellular methylation, potentially contributing to their cytotoxic effects.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- 6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine antimetabolites.
- Both drugs are metabolized to methylthio-IMP (Me-tIMP), a potent inhibitor of de novo purine synthesis.
- S-adenosylmethionine (S-Ado-Met) is a crucial methyl donor for various cellular macromolecules.
Purpose of the Study:
- To investigate the effects of 6-MP and Me-MPR on intracellular concentrations of S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine, and methionine.
- To elucidate the impact of these purine antimetabolites on cellular methylation status.
- To explore potential mechanisms of cytotoxicity related to altered methylation.
Main Methods:
- Measurement of S-Ado-Met, S-Ado-Hcy, homocysteine, and methionine concentrations in Molt F4 human malignant lymphoblasts.
- Analysis of the metabolic pathways involving 6-MP, Me-MPR, and S-Ado-Met.
- Assessment of ATP levels and their correlation with S-Ado-Met synthesis.
Main Results:
- Both 6-MP and Me-MPR significantly decreased intracellular S-Ado-Met concentrations.
- A notable increase in S-Ado-Hcy and methionine levels was observed following drug treatment.
- The observed effects were linked to ATP depletion, inhibiting methionine adenosyltransferase activity and thus S-Ado-Met formation.
Conclusions:
- 6-MP and Me-MPR disrupt the cellular methylation balance by depleting S-Ado-Met.
- This depletion is a consequence of inhibited purine synthesis leading to ATP depletion.
- Altered cellular methylation may represent an additional mechanism contributing to the cytotoxicity of these purine antimetabolites.