Metabolism of the neurotoxic amino acid β-N-methylamino-L-alanine in human cell culture models

• Published in: Toxicon (Oxford) 2019-10, Vol.168, p.131-139
• Main Authors: Downing, Simoné, Van Onselen, Rianita, Kemp, Gabré, Downing, Timothy Grant
• Format: Article
• Language: English
• Subjects: Amino Acids - metabolism; Amino Acids, Diamino - metabolism; Amino Acids, Diamino - toxicity; Apoptosis; Bioavailability; Biological Availability; BMAA; Caco-2 Cells; Cyanobacteria; Excitatory Amino Acid Agonists - metabolism; Excitatory Amino Acid Agonists - toxicity; Hep G2 Cells; Humans; Intestine, Small - metabolism; Liver - metabolism; Metabolism; Necrosis; Oral exposure; Oral toxicity; β-N-Methylamino-L-alanine
• ISSN: 0041-0101; 1879-3150
• DOI: 10.1016/j.toxicon.2019.07.007

Human dietary exposure to the environmental neurotoxin β-N-methylamino-L-alanine (BMAA) has been implicated in an increased risk of developing sporadic neurodegenerative diseases like Alzheimer's and amyotrophic lateral sclerosis. Evidence suggests that humans are exposed to BMAA globally, but very little is known about BMAA metabolism in mammalian systems, let alone in humans. The most plausible, evidence-based mechanisms of BMAA toxicity rely on the metabolic stability of the amino acid and that, following ingestion, it enters the circulatory system unmodified. BMAA crosses from the intestinal lumen into the circulatory system, and the small intestine and liver are the first sites for dietary amino acid metabolism. Both tissues have substantial amino acid metabolic needs, which are largely fulfilled by dietary amino acids. Metabolism of BMAA in these tissues has been largely overlooked, yet is important in gauging the true human exposure risk. Here we investigate the potential for BMAA metabolism by the human liver and small intestine, using in vitro cell systems. Data show that BMAA metabolism via common proteinogenic amino acid metabolic pathways is negligible, and that in the presence of other amino acids cellular uptake of BMAA is substantially reduced. These data suggest that the majority of ingested BMAA remains unmodified following passage through the small intestine and liver. This not only supports oral BMAA exposure as a plausible exposure route to toxic doses of BMAA, but also supports previous notions that protein deficient diets or malnutrition may increase an individual's susceptibility to BMAA absorption and subsequent toxicity. •BMAA metabolism via amino acid metabolic pathways is negligible in human cells.•In vitro BMAA metabolites in human cells differ from those produced in vivo in rats.•Low level BMAA metabolism produces L-alanine in a human liver cell model.•The majority of ingested BMAA remains unchanged in the small intestine and liver.•Amino acids substantially reduce BMAA uptake in liver and intestinal cells.