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Electrospray[+] Tandem Quadrupole Mass Spectrometry in The JOURNAL OF MASS SPECTROMETRY J. Mass Spectrom. 2005; 40: 1484–1502 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jms.933 Electrospray[+] tandem quadrupole mass spectrometry in the elucidation of ergot alkaloids chromatographed by HPLC: screening of grass or forage samples for novel toxic compounds†‡ Andreas F. Lehner,1∗ Morrie Craig,2 Neil Fannin,3 Lowell Bush3 and Tom Tobin4 1 University of Kentucky, College of Agriculture, Livestock Disease Diagnostic Center, Lexington, Kentucky, USA 40512 2 Oregon State University, College of Veterinary Medicine, Corvallis, Oregon, USA 97331 3 University of Kentucky, Department of Agronomy, Plant Science Building, Lexington, Kentucky, USA 40546 4 University of Kentucky, Department of Veterinary Science, Maxwell H. Gluck Equine Research Center, Lexington, Kentucky, USA 40546 Received 14 May 2005; Accepted 5 September 2005 Ergot alkaloids are mycotoxins generated by grass and grain pathogens such as Claviceps, for example. Ergot alkaloid–poisoning syndromes, such as tall fescue toxicosis from endophyte-infected tall fescue grass, are important veterinary problems for cattle, horses, sheep, pigs and chickens, with consequent impact on food, meat and dairy industries. Damage to livestock is of the order of a billion dollars a year in the United States alone. HPLC with UV and fluorescence detection are the predominant means of ergot alkaloid determination, with focus on quantitation of the marker compound ergovaline, although ELISA methods are undergoing investigation. These techniques are excellent for rapid detection, but of poor specificity in defining new or poorly characterized ergot alkaloids and related compounds. This paper demonstrates the facility of using electrospray(+) mass spectrometry with multiple reaction monitoring (MRM) detection during chromatographic examination of ergot alkaloid standards of lysergic acid, lysergol, ergonovine, ergovaline, ergotamine, ergocornine, ergocryptine and ergocrystine by HPLC. Ergoline-8 position epimers could be separated on the gradient HPLC system for ergocornine, ergocrystine and ergonovine and appeared as shoulders for ergotamine and ergovaline; epimers generally showed different patterns of relative intensity for specific MRM transitions. There was reasonable correspondence between retention of standards on the 2-mm ESI(+)MS phenyl-hexyl-based reverse phase column and those on the 4-mm C18-based column. Since up to 10% of clinical cases involving toxin exposure display unidentified chromatographic peaks, 11 samples of feed components associated with such cases were studied with developed MRM methods to attempt elucidation of crucial components if possible. Ergotamine appeared in all, ergovaline appeared in five and ergocornine appeared in six; ergonovine, ergocryptine, ergocrystine and lysergol also appeared in several. In addition, molecular weights of compounds newly revealed by mass spectrometry suggested ergosine, ergostine and ergoptine in four samples, for which standards were not available. Dehydrated products of ergotamine, ergocrystine and ergocornine were discovered, along with dihydrogenated ergocrystine and ergocryptine in seven of the samples, and the issue was raised as to whether dehydration was strictly an instrument-derived artifact. Finally, five of the samples, along with fescue seed standard, evidenced one or more of 14 new ergot alkaloids ranging in size from 381 to 611 molecular weight and with key mass spectral characteristics of ergot alkaloids, specifically the pair of peaks m/z 223 and 208, corresponding to the ergoline ring system and its demethylated variant, respectively. It is anticipated that findings such as these will provide impetus to future development of analytical methodology for these heretofore relatively rare ergot alkaloid species. Copyright 2005 John Wiley & Sons, Ltd. KEYWORDS: ergot alkaloids; ergotoxins; ergovaline; LC/MS/MS; electrospray(C) mass spectrometry ŁCorrespondence to: Andreas F. Lehner, University of Kentucky, Livestock Disease Diagnostic Center, Lexington, Kentucky, USA 40512-4125. E-mail: [email protected] †Published as # 305 from the Equine Pharmacology Therapeutics and Toxicology Program at the Maxwell H. Gluck Equine Research Center and Department of Veterinary Science, University of Kentucky. ‡Published as Kentucky Agricultural Experiment Station Article # 04-14-095 with the approval of the Dean and Director, College of Agriculture and the Kentucky Agricultural Experimental Station. Contract/grant sponsor: USDA; Contract/grant number: 58-6401-2-0025 and Cooperative Agreement number 58-6227-4-0021. Contract/grant sponsor: Kentucky Department of Agriculture. Contract/grant sponsor: Kentucky Thoroughbred Association Foundation. Contract/grant sponsor: Horsemen’s Benevolent and Protective Association. Contract/grant sponsor: Mrs John Hay Whitney. Copyright 2005 John Wiley & Sons, Ltd. HPLC-ESI-MS/MS of ergot alkaloids 1485 INTRODUCTION central amide oxygen; see the section ‘Discussion’ for more information on this topic. Ergot alkaloids or ergotoxins are mycotoxins that have Barber et al.3 first reported application of mass spec- contributed to human diseases since antiquity (for review trometry to both ergopeptide (C9–C10 double bond) and see Ref. 1). Common grass pathogens known as Claviceps that non-peptide-containing clavine (saturated at C10, generally contaminate grains are responsible for causing gangrenous with C8–C9 double bond) alkaloids in which they observed or convulsive forms of ergotism, which affect the blood relatively strong molecular ions and M-1 base peaks with the supply to extremities or to the central nervous system, clavine-type compounds, and more extensive and sequential respectively. Although modern methods of grain cleaning series of fragmentations with the ergopeptides, as visualized have largely eliminated ergotism as a human disease, it is on a double-focusing high-resolution MS with a direct inser- still an important veterinary problem, with principal victims tion probe and with a relatively mild 16-eV electron energy. including cattle, horses, sheep, pigs and chickens. Clinical Voigt et al.4 applied electron impact mass spectrometry (EI- signs include gangrene, abortion, convulsions, suppression MS) to similar clavines and ergopeptides via direct insertion of lactation, hypersensitivity and ataxia. probe to compare positive and negative ion modes, and In general, plant material including grasses contain a dependably found ergopeptide M and M-1 ions more eas- number of alkaloids of agricultural significance, some of ily by negative mode than by positive mode. Vokoun et al.5 which have been isolated and characterized and many carried out similar direct insertion EI-MS of 8–9, 9–10 and others of which remain undefined. Of particular interest C8–9–10-saturated clavines, which displayed intense MC are perennial ryegrass (Lolium perenne) and tall fescue ions, and ergopeptides, which did not, confirming the work grass (Festuca arundinacea Schreb). For example, it has been of Barber et al.;3 spectra of C-8 epimers were considered indis- found that perennial ryegrass contains not only the lolitrem tinguishable from one another. Porter and Betowski6 further alkaloids but also ergovaline, the common ergotoxin in expanded the repertoire of applied mass spectrometric tech- tall fescue. Concentrations of the lolitrem alkaloids and niques in reporting deconvolution of chemical ionization (CI) ergovaline have shown positive correlation with one another mass spectra of ergot alkaloids, claiming it a successful sup- (r2 D 0.7335), i.e. if one is high, the other is also likely plementary technique to EI-MS which typically eliminates to be.2 However, clinical cases of fescue toxicosis have the molecular ion. also been associated with tall fescue grasses containing Eckers et al.7,8 applied HPLC coupled via moving belt substances that produce undefined and unidentified HPLC interface to EI- and CI-MS to identify 11 known alkaloids chromatographic peaks, possibly ergotoxins with structures in chloroform extracts of Claviceps purpurea; this represented related to ergovaline. a step forward since HPLC is more amenable to clavine The general structures of ergot alkaloids under consid- and ergopeptide compounds than GC. In a similar chro- eration are presented in Fig. 1, with more complex analogs matographic advance, Porter’s group9 combined thin-layer incorporating both lysergic, i.e. ergoline, and peptide ring chromatography with both EI- and CI-MS by introduction systems as shown to give ergopeptides, and simpler analogs of extracts from C. purpurea sclerotia by direct insertion to such as lysergic acid including only the lysergic ring sys- identify nine alkaloids in fescue, barley and wheat, with esti- tem with far simpler C-8 substituents. Solvent-, pH- or mation of relative peptide alkaloid percentages from MS/MS temperature-induced epimerization between carbon-8 ˇ and data using the relative ratios of respective signals for the ˛ versions occurs at the lysergic ring C-8 position, most major daughter ion fragments. Porter10 subsequently sum- likely arising as the result of keto-enol tautomerism at the marized isobutane CI-MS parameters for 15 ergot alkaloids Figure 1. Ergot alkaloid general structure, including stereochemistry and crucial position numbering and ring labeling (rings A–D constitute lysergic or ergoline; E–G, peptide ring systems). R1 and R2 alkyl and aralkyl substituents are listed in tabular form with corresponding compound names;
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