Cytotoxicity and fluorescence visualization of ergot alkaloids in human cell lines.

The ergot alkaloids as secondary metabolites from fungi of the genus Claviceps are the focus of many investigations because of their pharmacological and toxicological properties. The main effects of ergot alkaloids are referred to an interaction with several receptor systems in the human body. It is well-known that ergot alkaloids are able to isomerize with one isomer being biologically active and one being only weakly active, whereas the activity is restricted to receptor interactions. Latest investigations have proven that ergot alkaloids also show cytotoxic effects and induce apoptosis in human primary cells. These effects seem to correlate with accumulation properties. It was the aim of our current study to determine such effects in cancer cell lines, because ergot derivatives are also used in tumor therapy. Our results confirm the apoptotic effects in two cancer cell lines (HepG2 and HT-29) in a high range, and accumulation measurements show an interesting correlation between the alkaloid concentration in the cell lysate of the receptor-inactive isomers and cytotoxicity. In addition, the strong accumulative effects were first visualized by fluorescence microscopy by taking advantage of the natural fluorescence properties of ergot alkaloids.

[1]  M. Gekle,et al.  Identification and apoptotic potential of T-2 toxin metabolites in human cells. , 2012, Journal of agricultural and food chemistry.

[2]  H. Humpf,et al.  Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity , 2011, Molecular nutrition & food research.

[3]  H. Humpf,et al.  Investigation of the metabolism of ergot alkaloids in cell culture by fourier transformation mass spectrometry. , 2011, Journal of agricultural and food chemistry.

[4]  H. Humpf,et al.  Cytotoxicity and accumulation of ergot alkaloids in human primary cells. , 2011, Toxicology.

[5]  H. Humpf,et al.  Ricinoleic acid as a marker for ergot impurities in rye and rye products. , 2010, Journal of agricultural and food chemistry.

[6]  G. Aiken,et al.  Bioaccumulation of ergovaline in bovine lateral saphenous veins in vitro. , 2009, Journal of animal science.

[7]  M. Appelt,et al.  Investigations into the occurrence of alkaloids in ergot and single sclerotia from the 2007 and 2008 harvests , 2009, Mycotoxin Research.

[8]  M. Gekle,et al.  Metabolism and cytotoxic effects of T-2 toxin and its metabolites on human cells in primary culture. , 2009, Toxicology.

[9]  H. Humpf,et al.  Large-scale production of selected type A trichothecenes: the use of HT-2 toxin and T-2 triol as precursors for the synthesis of d3-T-2 and d3-HT-2 toxin , 2009, Mycotoxin Research.

[10]  A. Akaike,et al.  Bromocriptine, a dopamine D(2) receptor agonist with the structure of the amino acid ergot alkaloids, induces neurite outgrowth in PC12 cells. , 2008, European journal of pharmacology.

[11]  P. Baumgart,et al.  Vaskulärer Ergotismus durch Getreidestaubinhalation , 2008 .

[12]  R. Krska,et al.  Stability and epimerisation behaviour of ergot alkaloids in various solvents , 2008 .

[13]  M. Gekle,et al.  Cytotoxicity, metabolism and cellular uptake of the mycotoxin deoxynivalenol in human proximal tubule cells and lung fibroblasts in primary culture. , 2007, Toxicology.

[14]  P. Schiff.  Ergot and its alkaloids. , 2006, American journal of pharmaceutical education.

[15]  A. Lampen,et al.  „ „Mutterkornalkaloide in Lebensmitteln“ , 2006, Journal für Verbraucherschutz und Lebensmittelsicherheit.

[16]  A. Craig,et al.  Growth and hepatic in vitro metabolism of ergotamine in mice divergently selected for response to endophyte toxicity , 2005, Xenobiotica; the fate of foreign compounds in biological systems.

[17]  J. Rosenthaler,et al.  Ergot alkaloids: Hepatic distribution and estimation of absorption by measurement of total radioactivity in bile and urine , 1976, Journal of Pharmacokinetics and Biopharmaceutics.

[18]  R. Markstein.  Neurochemical effects of some ergot derivatives: A basis for their antiparkinson actions , 2005, Journal of Neural Transmission.

[19]  F. Hata,et al.  The interactions of bromocriptine and lergotrile with dopamine and α-adrenergic receptors , 2005, Journal of Neural Transmission.

[20]  O. N. Tolkachev,et al.  The Chemistry of Peptide Ergot Alkaloids. Part 1. Classification and Chemistry of Ergot Peptides , 2001, Pharmaceutical Chemistry Journal.

[21]  E. Silbergeld,et al.  Binding of antiparkinsonian ergot derivatives to the dopamine receptor , 1981, Psychopharmacology.

[22]  W. Ruch,et al.  Bromocriptine, dihydroergotoxine, methysergide, d-LSD, CF 25-397, and 29-712: Effects on the metabolism of the biogenic amines in the brain of the rat , 1978, Psychopharmacology.

[23]  G. Maurer,et al.  Elucidation of the structure and receptor binding studies of the major primary, metabolite of dihydroergotamine in man , 2004, European Journal of Clinical Pharmacology.

[24]  M. Namba,et al.  Establishment of the transformants expressing human cytochrome P450 subtypes in HepG2, and their applications on drug metabolism and toxicology. , 2001, Toxicology in vitro : an international journal published in association with BIBRA.

[25]  P R Saxena,et al.  Ergotamine in the acute treatment of migraine: a review and European consensus. , 2000, Brain : a journal of neurology.

[26]  B. Larson,et al.  Alkaloid binding and activation of D2 dopamine receptors in cell culture. , 1999, Journal of animal science.

[27]  D. Richel,et al.  Apoptosis and secondary necrosis of lymphocytes in culture. , 1997, Acta haematologica.

[28]  J. T. Turner,et al.  Ergovaline binding and activation of D2 dopamine receptors in GH4ZR7 cells. , 1995, Journal of animal science.

[29]  M. Grant,et al.  The influence of culture medium composition on drug metabolising enzyme activities of the human liver derived Hep G2 cell line , 1988, FEBS letters.

[30]  J. T. Turner,et al.  Alpha 2-adrenergic receptors in the human cell line, HT29. Characterization with the full agonist radioligand [3H]UK-14,304 and inhibition of adenylate cyclase. , 1985, Molecular pharmacology.

[31]  G. Jennings,et al.  Bioavailability of dihydroergotamine in man. , 1982, British journal of clinical pharmacology.

[32]  J. Young.  Variability in the content and composition of alkaloids found in Canadian ergot. I. Rye. , 1981, Journal of environmental science and health. Part. B, Pesticides, food contaminants, and agricultural wastes.

[33]  P. Scott,et al.  Analysis of ergot alkaloids in flour. , 1980, Journal of agricultural and food chemistry.

[34]  W. H. Aellig,et al.  Ergot Alkaloids and Related Compounds , 1978, Handbook of Experimental Pharmacology / Handbuch der experimentellen Pharmakologie.

[35]  A. Stoll,et al.  Über Belichtungsprodukte von Mutterkornalkaloiden. 39. Mitteilung über Mutterkornalkaloide , 1955 .

[36]  H. Dale.  On some physiological actions of ergot , 1906, The Journal of physiology.