Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo

S. P. Perrine, George J Dover, P. Daftari, C. T. Walsh, Y. X. Jin, A. Mays, D. V. Faller

Research output: Contribution to journalArticle

Abstract

Butyrate and other short-chain fatty acids stimulate fetal globin gene expression and have potential for ameliorating the P globin disorders. Butyrate, however, is rapidly metabolized in vivo and reaches only micromolar concentrations in plasma. We report here that a branched-chain derivative of butyrate, isobutyramide, increases γ globin gene expression in cultured human erythroid progenitors in vitro and stimulates activity from a minimal γ globin gene promoter linked to a reporter gene in stable and transient expression assays, with slightly less activity in these in vitro assays than butyrate. In vivo, administration of isobutyramide to anaemic adult baboons rapidly stimulates fetal globin synthesis and F-reticulocyte production. Plasma concentrations at millimolar levels are achieved after a single intravenous or oral dose (500-600 mg/kg), and these concentrations are maintained for 9.5-10.5 h. These results indicate that although isobutyramide has slightly less activity than butyrate in vitro in enhancing fetal globin expression at the cellular and molecular level, its prolonged in vivo half-life may provide superior activity as a therapeutic agent for reactivating fetal globin gene expression in vivo.

Original languageEnglish (US)
Pages (from-to)555-561
Number of pages7
JournalBritish Journal of Haematology
Volume88
Issue number3
StatePublished - 1994
Externally publishedYes

Fingerprint

Globins
Butyrates
Gene Expression
Volatile Fatty Acids
Papio
Reticulocytes
isobutyramide
In Vitro Techniques
Reporter Genes
Half-Life
Genes

Keywords

  • Butyrate analogue
  • Fetal haemoglobin
  • Gene induction

ASJC Scopus subject areas

  • Hematology

Cite this

Perrine, S. P., Dover, G. J., Daftari, P., Walsh, C. T., Jin, Y. X., Mays, A., & Faller, D. V. (1994). Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo. British Journal of Haematology, 88(3), 555-561.

Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo. / Perrine, S. P.; Dover, George J; Daftari, P.; Walsh, C. T.; Jin, Y. X.; Mays, A.; Faller, D. V.

In: British Journal of Haematology, Vol. 88, No. 3, 1994, p. 555-561.

Research output: Contribution to journalArticle

Perrine, SP, Dover, GJ, Daftari, P, Walsh, CT, Jin, YX, Mays, A & Faller, DV 1994, 'Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo', British Journal of Haematology, vol. 88, no. 3, pp. 555-561.
Perrine, S. P. ; Dover, George J ; Daftari, P. ; Walsh, C. T. ; Jin, Y. X. ; Mays, A. ; Faller, D. V. / Isobutyramide, an orally bioavailable butyrate analogue, stimulates fetal globin gene expression in vitro and in vivo. In: British Journal of Haematology. 1994 ; Vol. 88, No. 3. pp. 555-561.
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