Tissue Specific Distribution and Activation of Sapindaceae Toxins in Horses Suffering from Atypical Myopathy

SIMPLE SUMMARY: Equids kept at pasture are at risk of being intoxicated by ingesting sycamore maple seeds or seedlings, which contain the two non-proteinogenic amino acids hypoglycin A and methylenecyclopropylglycine. These amino acids are converted into effective toxins by metabolic processes, inducing severe damage to oxidative muscles. Toxic metabolites are known to disrupt the cellular use of important energy sources such as short- and medium-chain fatty acids or branched-chain amino acids. The comparative examination of different tissues from five horses that died from this environmental intoxication named atypical myopathy revealed that the highest concentration of active toxins was found in muscles. In all the tissues analyzed, there was still unmetabolized hypoglycin A, which suggests that inhibiting the conversion of protoxins into toxic metabolites would be a possible therapeutic approach. ABSTRACT: Equine atypical myopathy is caused by hypoglycin A (HGA) and methylenecyclopropylglycine (MCPrG), the known protoxins of sycamore maple (Acer pseudoplatanus). Various tissues from five atypical myopathy cases were analyzed but only HGA was found. Whether deamination of MCPrG has already occurred in the intestine as the first stage of metabolization has not been investigated. Activation of the protoxins to methylenecyclopropylacetyl (MCPA)-CoA and methylenecyclopropylformyl (MCPF)-CoA, respectively, occurred mainly in the skeletal muscles, as evidenced by very high concentrations of MCPA-carnitine and MCPF-carnitine in this tissue. Inhibition of the acyl-CoA dehydrogenases of short- and medium-chain as well as branched-chain fatty acids by the toxins led to a strong increase in the corresponding acylcarnitines, again preferentially in skeletal muscles. An accumulation of the long-chain acylcarnitines beyond the level of the control samples could not be detected in the tissues. As a high amount of HGA was always found unmetabolized in the organs, we speculate that targeting the interruption of further metabolization might be a way to stop the progression of intoxication. Inhibition of the mitochondrial branched-chain amino acid aminotransferase, i.e., the first enzyme responsible for the activation of sycamore maple protoxins, could be a therapeutic approach.