Investigation of the Ergopeptide Epimerization Process

Andrae, K.; Merkel, Stefan; Durmaz, Vedat; Fackeldey, Konstantin; Köppen, Robert; Weber, Marcus; Koch, Matthias

doi:10.3390/computation2030102

Cited by 13 publications

(9 citation statements)

References 32 publications

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“…However, this transformation was unlikely. The reason being, the transformation of the ( S ) to ( R )-epimer is not favored and the ( S )-epimer slightly dominates the equilibrium ( Andrae et al, 2014 ). The ( S )-epimer would have to undergo a more difficult rearrangement to switch to the intermediate and, therefore, the ( R )-epimer.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro

Cherewyk

Parker

Blakley

et al. 2020

Journal of Animal Science

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Abstract Ergot alkaloids are produced by the fungus Claviceps purpurea and their levels are carefully monitored in animal and human diets due to their harmful effects and widespread contamination of cereal crops. Ergot alkaloids exist in two forms known as the (R) and (S)-epimer with only the former being monitored in diets in North America. The (S)-epimers of ergot alkaloids are thought to be biologically inactive and, therefore, harmless. A major mechanism by which the (R)-epimers of ergot alkaloids produce their toxic effect is through vasoconstriction. Therefore, the objective of this study was to examine the vasoactivity potential (contractile response) of four (S)-epimers; namely ergocryptinine, ergocristinine, ergocorninine and ergotaminine utilising an in vitro arterial tissue bath system. Bovine metatarsal arteries (n=6, ergocryptinine and ergocorninine; n=6, ergocristinine and ergotaminine, n=6 arteries/(S)-epimer, total n=12) were collected from healthy mixed breed beef steers immediately after slaughter, cut into 3mm arterial cross sections and suspended in a tissue bath with continuously oxygenated Krebs-Henseleit buffer. To assess the contractile response of each (S)-epimer, a cumulative contractile dose response curve was constructed by incubating arteries with increasing concentrations (1 × 10-11M to 1 × 10-6M) of that (S)-epimer. Contractile responses were recorded as grams of tension and were normalized to an initial contraction of phenylephrine (PE). Contrary to the widespread belief, all tested (S)-epimers were found vasoactive and produced a concentration-dependent arterial contractile response similar to what has been reported for the (R)-epimers. The arterial contractile response to ergotaminine was strongest and was significantly greater than that of ergocryptinine and ergocristinine at the highest concentration used (P ≤ 0.01). Our results indicate that the (S)-epimers are biologically active and are likely harmful similar to the (R)-epimers. The levels of (S)-epimers should be carefully monitored in human and animal diets worldwide.

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Section: Discussionmentioning

confidence: 99%

Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro

Cherewyk

Parker

Blakley

et al. 2020

Journal of Animal Science

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“…Another goal of the present work was to establish the validity of using simple isothermal adsorption characteristics to predict potential physiological effects after adsorption. This relationship could be confounded by epimerization of ETA, which is influenced by pH, heat and light, resulting in potential differences in the ratio of biologically active (R-) to inactive (S-) forms of ETA [ 45 , 46 , 47 ]. Although isomeric ratios could be determined analytically (e.g., with LC-MS/MS), extraction conditions (extraction solvents, pH, time of extraction, effects of heat and temperature) would render interpretation challenging.…”

Section: Discussionmentioning

confidence: 99%

Contractile Response of Bovine Lateral Saphenous Vein to Ergotamine Tartrate Exposed to Different Concentrations of Molecularly Imprinted Polymer

Kudupoje

Klotz

Yiannikouris

et al. 2018

Toxins

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Ergot alkaloids, in their active isomeric form, affect animal health and performance, and adsorbents are used to mitigate toxicities by reducing bioavailability. Adsorbents with high specificity (molecularly imprinted polymers: MIP) adsorb ergot alkaloids in vitro, but require evaluation for biological implications. Using ex vivo myography, synthetic polymers were evaluated for effects on the bioactivity of ergotamine tartrate (ETA). Polymers were first evaluated using isotherms. Lateral saphenous veins were collected from 17 steers for four independent studies: dose response of ETA, adsorbent dose response, validation of pre-myograph incubation conditions and MIP/ non-molecularly imprinted polymer (NIP) comparison. Norepinephrine normalized percent contractile response to increasing ETA exhibited a sigmoidal dose response (max: 88.47 and log of the effective molar concentration (EC50) (−log [ETA]) of 6.66 ± 0.17 M). Although sample preparation time affected contractile response (p < 0.001), pre-myograph incubation temperature (39 vs. 21 °C, 1 h) had no effect (p > 0.05). Isothermal adsorption showed a maximum adsorption of 3.27E-008 moles·mg−1 and affinity between 0.51 and 0.57 mg (R2: 0.83–0.92) for both polymers, with no significant difference between polymers (p > 0.05). No significant differences in maximum inhibitory (p = 0.96) and IC50 responses (p = 0.163) between MIP and NIP were noticed. Normalized percent contraction could be predicted from the in vitro adsorption data (R2 = 0.87, p < 0.01), for both polymers. These studies indicate that synthetic polymers are potentially effective adsorbents to mitigate ergot toxicity caused by ergot alkaloids, with little evidence of significant differences between MIP and NIP in aqueous media.

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“…Consequently, storage conditions (best below −20 °C), handling and analysis need to be consistent to avoid altering alkaloid epimerization [ 6 ]. While ergot alkaloids produce a positive charge in acid solutions and are neutral in alkali [ 19 ], the actual mechanisms leading to conversion between epimeric forms are unknown [ 20 ]. In addition, epimerization can be bi-directional in ergopeptines (i.e., ergometrine, ergotamine, ergosine, ergocristine, ergocryptine and ergocornine), either forming toxic C8-( R ) isomers or more inert C8-( S ) isomers referred to as ergopeptinines [ 21 ], although S epimers may also produce toxic effects [ 22 ], and the toxicity of S epimers requires additional investigation.…”

Section: Discussionmentioning

confidence: 99%

Effects of Continuously Feeding Diets Containing Cereal Ergot Alkaloids on Nutrient Digestibility, Alkaloid Recovery in Feces, and Performance Traits of Ram Lambs

Coufal-Majewski

Stanford

McAllister

et al. 2017

Toxins

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Allowable limits for cereal ergot alkaloids in livestock feeds are being re-examined, and the objective of this study was to compare nutrient digestibility, growth performance and carcass characteristics of ram lambs fed a range of alkaloid concentrations, including the maximum currently allowed in Canada (2 to 3 ppm). Four pelleted diets were fed: control, with no added alkaloids; 930; 1402; and 2447 ppb alkaloids based on total R and S epimers. Eight ram lambs (30.0 ± 3.1 kg) were used to examine the impacts of dietary treatments on nutrient digestibility and alkaloid recovery from feces. Concentrations of dietary alkaloids evaluated did not affect nutrient digestibility or N metabolism. Excepting ergocornine and ergocryptine, recovery of alkaloids in feces varied among periods, suggesting that individual lambs may differ in their ability to metabolize ergocristine, ergometrine, ergosine, ergotamine and their S epimers. In a second experiment, ram lambs (n = 47, 30 ± 8 kg) were randomly assigned to a diet and weighed weekly until they achieved a slaughter weight of ≥ 45 kg (average 9 weeks; range 6 to 13 weeks). Intake of DM did not differ (p = 0.91) among diets, although lambs fed 2447 ppb alkaloids had a lower (p < 0.01) ADG than did lambs receiving other treatments. The concentration of serum prolactin linearly declined (p < 0.01) with increasing alkaloids. Feeding 2447 ppb total alkaloids negatively impacted growth, while feeding 1402 ppb did not harm growth performance, but reduced carcass dressing percentage. Due to different concentrations of alkaloids affecting growth and carcass characteristics in the present study, determining allowable limits for total dietary alkaloids will require a better understanding of impacts of alkaloid profiles and interactions among individual alkaloids.

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Investigation of the Ergopeptide Epimerization Process

Cited by 13 publications

References 32 publications

Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro

Assessment of the vasoactive effects of the (S)-epimers of ergot alkaloids in vitro

Contractile Response of Bovine Lateral Saphenous Vein to Ergotamine Tartrate Exposed to Different Concentrations of Molecularly Imprinted Polymer

Effects of Continuously Feeding Diets Containing Cereal Ergot Alkaloids on Nutrient Digestibility, Alkaloid Recovery in Feces, and Performance Traits of Ram Lambs

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