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Pitfalls related to Dibutyryl cyclic AMP and -cGMP

- The Potential Biological Effects of Butyrate -

Both, dibutyryl cyclic AMP and cyclic GMP (DB-cAMP, DB-cGMP) are common and widely used tools for proving the responsibility of cAMP and cGMP, respectively, for certain biological effects. However, in spite of the intensive use of these second messenger analogs there exist serious pitfalls which can falsify the results obtained with them.

In their native form both analogs are nearly inactive towards protein kinase A and G, and need to split off one of their butyryl groups at the ribose 2'- position in order to release the kinase-active monobutyryl cAMP/cGMP. Induced by esterases, this should normally take place inside the cell, but can also happen already in the medium if serum is used.

Unfortunately, the released butyrate induces a lot of effects which are often interfering with second messenger pathways.That means, that for each experiment with DB-cAMP and DB-cGMP, the influence of butyrate has to be determined in control runswith sodium butyrate or tributyrin.

Today, a lot of much more potent and selective cAMP/cGMP agonists are available, which avoid trouble with butyrate. Please do not hesitate to contact us for further information.

The following effects of butyrate are documented (selection):

Butyrate as a stimulator of gene expression:
Hypomethylated globin(2), β-adrenergic receptor(3), alkaline phosphatase(4), choriongonadotropin(3) , estrogen receptor(5), chromatin-associated protein kinase(6,13,16)

Butyrate as differentiating agent: Neoplasm inhibition(7,8), cytoarchitectural reorganization(8), plasminogen activator & inhibitor(10), interleukin 6-induced differentiation(11)

Butyrate disturbs the focus on PKA/ PKG pathway: Stimulation of PKC(17), induction of expression of PKC isoforms(18), abolishes the mitogenic action of forskolin(22), modulates cyclic GMP level (23).

Butyrate as inhibitor of histone deacetylation (HDAC): Protein phosphatase involved (18,19,24)

Butyrate induces and potentiates apoptosis: Induction of apoptosis(19, 20), potentiation of chemotherapy-induced apoptosis(21)



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Crane, J.K.; Shanks, K.L.; Majumdar, S., Arch. Biochem. Biophys., 376, 163 - 170 (2000): "Redistribution of Cyclic GMP in Response to Sodium Butyrate in Colon Cells"


Sjöholm, A.; Diabetes 46, 1141 - 1147 (1997): "Glucose Stimulates Islet β-Cell Mitogenesis Through GTP Binding Proteins and by Protein Kinase C-Dependent Mechanisms"


Conway, R.M.; Madigan, M.C.; Billson, F.A.; Penfold, P.L.; Europ. J. Cancer, 34, 1741 - 1748, (1998): "Vincristine- and Cisplatin-induced Apoptosis in Human Retinoblastoma - Potentiation by Sodium Butyrate"


Soldatenkov, V.A.; Prasad, S.; Voloshin, Y.; Dritschilo, A.; Cell Death Differentiation, 5, 307 - 312 (1998): "Sodium Butyrate Induces Apoptosis and Accumulation of Ubiquitinated Proteins in Human Breast Carcinoma Cells"


Salminen, A.; Tapiola, T.; Korhonen, P.; Suuronen, T.; Mol. Brain Res., 61, 203 - 206 (1998): "Neuronal Apoptosis Induced by Histone Deacetylase Inhibitors"


Cuisset, L.; Tichonicky, L.; Delpech, M., Biochem. & Biophys. Res. Commun., 246, 760 - 764 (1998): "A Protein Phosphatase is Involved in the Inhibition of Histone Deacetylation by Sodium Butyrate"


Rivero, J.A.; Adunyah, S.E.; Biochem. Biophys. Res.Commun., 248, 664 - 668 (1998): "Sodium Butyrate Stimulates PKC Activation and Induces Differential Expression of Certain PKC Isoforms During Erythroid Differentiation"


Feng, P.; Ge, L.; Akyhani, N.; Liau, G.; Cell Dev.Biol., 29, 231 - 241 (1996): "Sodium Butyrate is a Potent Modulator of Smooth Muscle Cell Proliferation and Gene Expression"


Kitaoka, H.; Ohya, K., J. Chromatogr., 238, 495 - 499 (1982): "Determination of Sodium N6, O- 2' - Dibutyryladenosine Cyclic 3', 5' -(Hydrogenphosphate) and its Hydrolysis Products by High-Performance Liquid Chromatography"


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Ladoux, A.; Damais, C.; Krawice, I.; Abita, J.; Frelin, C.; FEBS Lett., 234, 353 (1988): "An Increase in Intracellular pH is a General Response of Promonocytic Cells to Differentiating Agents"


Staecker, J.L.; Pitot, H.C.; Arch. Biochem.Biophys., 261, 291 (1988): "The Effect of Sodium Butyrate on Tyrosine Aminotransferase Induction in Primary Cultures of Adult Rat Hepatocytes"


Kawamoto, T.; Gohda, E.; Fujiwara, M.; Yamamoto, I.; Immunopharmacology 40, 119 -130 (1998): "SKW 6.4 Cell Differentiation Induced by Interleukin 6 is Stimulated by Butyrate"


Gross, J.L.; Behrens, D.L.; Mullins, D.E.; Kornblith, P.L.; Dexter, D.L.; Cancer Res., 48, 291 (1988): "Plasminogen Activator and Inhibitor Activity in Human Glioma Cells and Modulation by Sodium Butyrate"


Ryan, M.P.; Borenfreund, E.; Higgins, P. J.; J. Natl. Cancer Inst., 79, 555 (1987): "Butyrate- Induced Cytoarchitectura Reorganization of Mallory Body-containing Rat Hepatic Tumor Cells"


Hutt-Taylor, S.R.; Harnish, D.; Richardson, M.; Ishizaka, T.; Denburg, J.A..; Blood, 71, 209 (1988): "Sodium Butyrate and a T Lymphocyte Cell Line-Derived Differentiation Factor Induce Basophilic Differentiation of the Human Promyelocytic Leukemia Cell Line HL 60"


Joshi, S.S.; Sinangil, F.; Sharp, J.G.; Mathews, N.B.; Volsky, D.J.; Brunson, K.W.; Cancer Detect. Prev., 11, 405 (1988): "Effects of Differentiation Inducing Chemicals on in Vivo Malignancy and NK Susceptibility of Metastatic Lymphoma Cells"


Kitzis, A..; Tichonicky, L.; Defer, N.; Kruh, J.; Biochem. Biophys. Res. Commun., 97, 530 (1980): "Localization of Phosphoproteins and of Protein Kinases in Chromatin from Butyrate Treated HTC Cells"


Graham, K.A.; Buick, R.N.; J. Cell.Physiol., 136, 63 (1988): "Sodium Butyrate Induces Differentiation in Breast Cancer Cell Lines Expressing the Estrogen Receptor"


Tamura, R.N.; Cox, G.S.; Biochim. Biophys. Acta, 968, 151 (1988): "Effect of Pyrimidine Deoxynucleosides and Sodium Butyrate on Expression of the Glycoprotein Hormone a- Subunit and Placental Alkaline Phosphatase in HeLa Cells"


Stadel, J.M.; Nakada, M.T.; Crooke S.T.; Int. Congr. Ser.- Exerpta Med., 750 (Pharmacology), 17 (1987): "Molecular Mechanisms of ß-Adrenergic Receptor Regulation"


Burns, L.J.; Glauber, J.G.; Ginder, G.D.; Blood 72, 1536 (1988): "Butyrate Induces Selective Transcriptional Activation of a Hypomethylated Embryonic Globin Gene in Adult Erythroid Cells"


Yusta, B.; Ortiz-Caro, J.; Pascual, A.; Aranda, A..; J. Neurochem., 51, 1808 (1988): "Comparison of the Effects of Forskolin and Dibutyryl Cyclic AMP in Neurolastoma Cells: Evidence that Some of the Actions of Dibutyryl Cyclic AMP are Mediated by Butyrate"