Pyrrolizidine alkaloid toxicosis and hepatic encephalopathy in horses in Easter Island, Chile

Lohse, Jorge; Paredes, Enrique; González, Carlos; Koene, Marc; Mageed, Mahmoud

doi:10.4067/s0719-81322018000200107

Cited by 2 publications

(3 citation statements)

References 8 publications

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“…The research conducted from 2010 to 2015 further investigated this link, revealing a strong association between the consumption of C. grahamiana, particularly its monocrotaline content, and hepatic encephalopathy in affected horses. The evidence suggests a causal relationship between pyrrolizidine alkaloid ingestion and the manifestation of CH disease on Easter Island [ 26 ]. Also, CNS toxicity in animals is linked to monocrotaline poisoning from Crotalaria plants.…”

Section: Discussionmentioning

confidence: 99%

Identification of Antagonistic Action of Pyrrolizidine Alkaloids in Muscarinic Acetylcholine Receptor M1 by Computational Target Prediction Analysis

Abdalfattah,

Knorz,

Ayoobi

et al. 2024

Pharmaceuticals

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Pyrrolizidine alkaloids (PAs) are one of the largest distributed classes of toxins in nature. They have a wide range of toxicity, such as hepatotoxicity, pulmonary toxicity, neuronal toxicity, and carcinogenesis. Yet, biological targets responsible for these effects are not well addressed. Using methods of computational biology for target identification, we tested more than 200 PAs. We used a machine-learning approach that applies structural similarity for target identification, ChemMapper, and SwissTargetPrediction. The predicted targets with high probabilities were muscarinic acetylcholine receptor M1. The predicted interactions between these two targets and PAs were further studied by molecular docking-based binding energies using AutoDock and VinaLC, which revealed good binding affinities. The PAs are bound to the same binding pocket as pirenzepine, a known M1 antagonist. These results were confirmed by in vitro assays showing that PAs increased the levels of intracellular calcium. We conclude that PAs are potential acetylcholine receptor M1 antagonists. This elucidates for the first time the serious neuro-oncological toxicities exerted by PA consumption.

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Section: Discussionmentioning

confidence: 99%

Identification of Antagonistic Action of Pyrrolizidine Alkaloids in Muscarinic Acetylcholine Receptor M1 by Computational Target Prediction Analysis

Abdalfattah,

Knorz,

Ayoobi

et al. 2024

Pharmaceuticals

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“…Relatively high levels of dietary exposure to 1,2-dehydroPAs ( 1 ) by livestock, especially horses and cattle, consuming plants that produce 1,2-dehydroPAs ( 1 ), e.g. , Crotalaria incana, Crotalaria retusa, and Senecio brasiliensis, can cause hepatic encephalopathy characterized by Alzheimer type II astrocytes. ,− ,− Encephalopathy, presumably secondary to liver damage, has also been reported in humans exposed to 1,2-dehydroPAs. , While the development of hepatic encephalopathy is generally attributed to high levels of circulating ammonia associated with chronic liver disease/cirrhosis, − it is recognized that there is no “direct correlation between ammonia levels and the severity of hepatic encephalopathy” and other factors could sometimes also be involved . For example, “10% of patients with significant encephalopathy have normal serum ammonia levels” and “many patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy” .…”

Section: 2-dehydropyrrolizidine Alkaloid Toxicitymentioning

confidence: 99%

“…When consumed in relatively high concentrations, 1,2-dehydroPAs ( 1 ) are metabolized by specific hepatic CYP450 enzymes into biological alkylating agents that cause characteristic, rapidly fatal damage to the liver and lungs (Figure ). , They also cause fatal neurotoxicity (hepatic encephalopathy) − and diverse cancers. ,,,,− Currently occurring sporadic low-level dietary exposure to 1,2-dehydroPAs is however likely to be well below levels causing these rapidly fatal, acute liver, lung, and brain pathologies but could be sufficient to eventually cause persistent genetic mutations and biochemical damage in CNS cells, leading to MNDs/NDDs that sometimes also display associated liver − and lung ,,− , pathologies and the diverse, co-occurring cancers. − , …”

Section: Introductionmentioning

confidence: 99%

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

Edgar

Molyneux

Colegate

2022

Chem. Res. Toxicol.

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Sporadic motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), can be caused by spontaneous genetic mutations. However, many sporadic cases of ALS and other debilitating neurodegenerative diseases (NDDs) are believed to be caused by environmental factors, subject to considerable debate and requiring intensive research. A common pathology associated with MND development involves progressive mitochondrial dysfunction and oxidative stress in motor neurons and glial cells of the central nervous system (CNS), leading to apoptosis. Consequent degeneration of skeletal and respiratory muscle cells can lead to death from respiratory failure. A significant number of MND cases present with cancers and liver and lung pathology. This Perspective explores the possibility that MNDs could be caused by intermittent, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids (1,2-dehydroPAs) that are increasingly recognized as contaminants of many foods consumed throughout the world. Nontoxic, per se, 1,2-dehydroPAs are metabolized, by particular cytochrome P450 (CYP450) isoforms, to 6,7-dihydropyrrolizines that react with nucleophilic groups (−NH, −SH, −OH) on DNA, proteins, and other vital biochemicals, such as glutathione. Many factors, including aging, gender, smoking, and alcohol consumption, influence CYP450 isoform activity in a range of tissues, including glial cells and neurons of the CNS. Activation of 1,2-dehydroPAs in CNS cells can be expected to cause gene mutations and oxidative stress, potentially leading to the development of MNDs and other NDDs. While relatively high dietary exposure to 1,2-dehydroPAs causes hepatic sinusoidal obstruction syndrome, pulmonary venoocclusive disease, neurotoxicity, and diverse cancers, this Perspective suggests that, at current intermittent, low levels of dietary exposure, neurotoxicity could become the primary pathology that develops over time in susceptible individuals, along with a tendency for some of them to also display liver and lung pathology and diverse cancers co-occurring with some MND/NDD cases. Targeted research is recommended to investigate this proposal.

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Pyrrolizidine alkaloid toxicosis and hepatic encephalopathy in horses in Easter Island, Chile

Cited by 2 publications

References 8 publications

Identification of Antagonistic Action of Pyrrolizidine Alkaloids in Muscarinic Acetylcholine Receptor M1 by Computational Target Prediction Analysis

Identification of Antagonistic Action of Pyrrolizidine Alkaloids in Muscarinic Acetylcholine Receptor M1 by Computational Target Prediction Analysis

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

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