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Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line.

Publication ,  Journal Article
Funk, RS; van Haandel, L; Becker, ML; Leeder, JS
Published in: J Pharmacol Exp Ther
October 2013

Therapeutic and toxic response to low-dose methotrexate (MTX) in the treatment of autoimmune disease continues to be highly variable, resulting in a critical need to identify predictive biomarkers of response. Biomarker development has been hampered by an incomplete understanding of the molecular pharmacology of low-dose MTX. To address this issue, accumulation of the substrates for aminoimidazole carboxamide ribonucleotide transformylase (AICART) and thymidylate synthase (TS) was measured as markers of pharmacological activity of MTX in an erythroblastoid cell line. A 115-fold increase in the AICART substrate and anti-inflammatory mediator, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5'-monophosphate (ZMP), was observed following exposure to 10 nM MTX but subsequently decreased with increasing MTX concentrations, declining to baseline levels with 1000 nM MTX. In contrast, the TS substrate, 2'-deoxyuridine 5'-monophosphate disodium salt (dUMP), displayed concentration-dependent accumulation, increasing 29-, 342-, and 471-fold over baseline with 10, 100, and 1000 nM MTX, respectively. Cellular levels of dUMP correlated with levels of the parent drug (MTX-PG1; r = 0.66, P < 0.001) and its polyglutamates (MTX-PG2-6) (r = 0.81, P < 0.001), whereas cellular levels of ZMP were only moderately correlated with MTX-PG1 (r = 0.34, P < 0.01). In contrast, accumulation of ZMP at 10 nM MTX was associated with a 2.9-fold increase in the AICART inhibitor dihydrofolate (DHF), represented primarily by long-chain DHF polyglutamates. Selectivity, defined as the ratio of ZMP to dUMP, was maximal following exposure to 6 nM MTX. Characterizing the range of MTX concentrations that selectively promote ZMP accumulation while preserving pyrimidine biosynthesis may lead to optimization of low-dose MTX therapy.

Duke Scholars

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

October 2013

Volume

347

Issue

1

Start / End Page

154 / 163

Location

United States

Related Subject Headings

  • Ribonucleotides
  • Pharmacology & Pharmacy
  • Methotrexate
  • K562 Cells
  • Humans
  • Folic Acid Antagonists
  • Erythroblasts
  • Dose-Response Relationship, Drug
  • Aminoimidazole Carboxamide
  • 3214 Pharmacology and pharmaceutical sciences
 

Citation

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Funk, R. S., van Haandel, L., Becker, M. L., & Leeder, J. S. (2013). Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line. J Pharmacol Exp Ther, 347(1), 154–163. https://doi.org/10.1124/jpet.113.206672
Funk, Ryan S., Leon van Haandel, Mara L. Becker, and J Steven Leeder. “Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line.J Pharmacol Exp Ther 347, no. 1 (October 2013): 154–63. https://doi.org/10.1124/jpet.113.206672.
Funk RS, van Haandel L, Becker ML, Leeder JS. Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line. J Pharmacol Exp Ther. 2013 Oct;347(1):154–63.
Funk, Ryan S., et al. “Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line.J Pharmacol Exp Ther, vol. 347, no. 1, Oct. 2013, pp. 154–63. Pubmed, doi:10.1124/jpet.113.206672.
Funk RS, van Haandel L, Becker ML, Leeder JS. Low-dose methotrexate results in the selective accumulation of aminoimidazole carboxamide ribotide in an erythroblastoid cell line. J Pharmacol Exp Ther. 2013 Oct;347(1):154–163.
Journal cover image

Published In

J Pharmacol Exp Ther

DOI

EISSN

1521-0103

Publication Date

October 2013

Volume

347

Issue

1

Start / End Page

154 / 163

Location

United States

Related Subject Headings

  • Ribonucleotides
  • Pharmacology & Pharmacy
  • Methotrexate
  • K562 Cells
  • Humans
  • Folic Acid Antagonists
  • Erythroblasts
  • Dose-Response Relationship, Drug
  • Aminoimidazole Carboxamide
  • 3214 Pharmacology and pharmaceutical sciences