Research Article: Detection of MCPG metabolites in horses with atypical myopathy

Date Published: February 5, 2019

Publisher: Public Library of Science

Author(s): Mandy Bochnia, Johannes Sander, Joerg Ziegler, Michael Terhardt, Stefanie Sander, Nils Janzen, Jessika-M. V. Cavalleri, Aleksandra Zuraw, Monika Wensch-Dorendorf, Annette Zeyner, David A. Lightfoot.

http://doi.org/10.1371/journal.pone.0211698

Abstract

Atypical myopathy (AM) in horses is caused by ingestion of seeds of the Acer species (Sapindaceae family). Methylenecyclopropylacetyl-CoA (MCPA-CoA), derived from hypoglycin A (HGA), is currently the only active toxin in Acer pseudoplatanus or Acer negundo seeds related to AM outbreaks. However, seeds or arils of various Sapindaceae (e.g., ackee, lychee, mamoncillo, longan fruit) also contain methylenecyclopropylglycine (MCPG), which is a structural analogue of HGA that can cause hypoglycaemic encephalopathy in humans. The active poison formed from MCPG is methylenecyclopropylformyl-CoA (MCPF-CoA). MCPF-CoA and MCPA-CoA strongly inhibit enzymes that participate in β-oxidation and energy production from fat. The aim of our study was to investigate if MCPG is involved in Acer seed poisoning in horses. MCPG, as well as glycine and carnitine conjugates (MCPF-glycine, MCPF-carnitine), were quantified using high-performance liquid chromatography-tandem mass spectrometry of serum and urine from horses that had ingested Acer pseudoplatanus seeds and developed typical AM symptoms. The results were compared to those of healthy control horses. For comparison, HGA and its glycine and carnitine derivatives were also measured. Additionally, to assess the degree of enzyme inhibition of β-oxidation, several acyl glycines and acyl carnitines were included in the analysis. In addition to HGA and the specific toxic metabolites (MCPA-carnitine and MCPA-glycine), MCPG, MCPF-glycine and MCPF-carnitine were detected in the serum and urine of affected horses. Strong inhibition of β-oxidation was demonstrated by elevated concentrations of all acyl glycines and carnitines, but the highest correlations were observed between MCPF-carnitine and isobutyryl-carnitine (r = 0.93) as well as between MCPA- (and MCPF-) glycine and valeryl-glycine with r = 0.96 (and r = 0.87). As shown here, for biochemical analysis of atypical myopathy of horses, it is necessary to take MCPG and the corresponding metabolites into consideration.

Partial Text

Atypical myopathy (AM) of horses is a frequently fatal disease characterized by acute rhabdomyolysis in pastured horses that consume seeds of Acer spp. (e.g., Acer pseudoplatanus, Acer negundo) [1–5] that belong to the Sapindaceae family of plants. Very young horses are particularly affected [3, 4]. In human medicine, it is well known that fruits of Sapindaceae can be very poisonous [6–9]. Early and on-going studies of the chemical components of these plants have shown that seeds and arils of Sapindaceae (ackee, lychee, longan, mamoncillo fruits) may contain the toxins hypoglycin A (HGA) and the lower homologue of HGA, methylenecyclopropylglycine (MCPG) [7, 10–16]. For example, in 1976, cases of Jamaican vomiting sickness (JVS) were investigated and conclusively linked to HGA in ackee fruits [17]. In other Sapindaceae, HGA alone (longan fruit), and in combination with MCPG (lychee fruit), was isolated from the fruits [11, 18, 19]. However, not all members of the Sapindaceae family produce both toxins, which seems to be associated with the ripeness of the various fruits [20, 21]. The ingestion of ackee and lychee fruits led to the detection of the metabolic products of exposure to HGA and MCPG [16]. These specific urinary metabolites of HGA and MCPG are methylenecyclopropylacetyl-glycine (MCPA-glycine) and methylenecyclopropylformyl-glycine (MCPF-glycine), respectively.

So far, only HGA has been reported to cause AM in horses, although it has been known for a long time that fruits from Sapindaceae not only contain HGA but also the structural analogue MCPG [12]. Previous studies detailed the relationship between HGA content in seeds of Acer pseudoplatanus ingested by mainly younger horses (< 3 years) on pastures and the detectable concentrations of HGA and the toxic metabolites (MCPA-glycine and MCPA-carnitine) in serum and urine after developing AM [3, 4, 31–33]. The repeated observation of the prevalence in young horses has not yet been fully explained, but may be due to the fact that horses until the age of three years spend more time on pasture over the whole year and have a higher susceptibility because of the higher energy need during the growth period [31]. In this study, it has been demonstrated that in addition to HGA, MCPG is involved in Acer seed poisoning of horses. This finding has to be taken into account for the description of the exact pathomechanism of AM. A deeper insight into the pathogenesis is important from the point of view of applied veterinary medicine because only a precise understanding of pathogenetic mechanisms will lead to the development of a specific therapy, which is still missing.   Source: http://doi.org/10.1371/journal.pone.0211698

 

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