Abstract
As one of the typical Maillard reaction products, furosine has been widely reported in a variety of heat-processed food. Though furosine was shown to be toxic on organs, its toxicity mechanism is still unclear. The present study aimed to investigate the toxicity mechanism of furosine in liver tissue. An intragastric gavage mice model (42-day administration, 0.1/0.25/0.5 g/kg of furosine per day) and a mice primary hepatocyte model were employed to investigate the toxicity mechanism of furosine on mice liver tissue. A metabonomics analysis of mice liver, serum, and red blood cells (RBC) was performed. The special metabolic mediator of furosine, lysophosphatidylcholine 18:0 (LPC (18:0)) was identified. Then, the effect of the upstream gene phospholipase A2 gamma (PLA2-3) on LPC (18:0), as well as the effect of furosine (100 mg/L) on the receptor-interacting serine/threonine-protein kinase (RIPK)1/RIPK3/mixed lineage kinase domain-like protein (MLKL) pathway and inflammatory factors, was determined in liver tissue and primary hepatocytes. PLA2-3 was found to regulate the level of LPC (18:0) and activate the expression of RIPK1, RIPK3, P-MLKL, and of the inflammatory factors including tumor necrosis factor α (TNF-α) and interleukin (IL-1β), both in liver tissue and in primary hepatocytes. Upon treatment with furosine, the upstream sensor PLA2-3 activated the RIPK1/RIPK3/MLKL necroptosis pathway and caused inflammation by regulating the expression of LPC (18:0), which further caused liver damage.
Highlights
The Maillard reaction is one of the most important reactions resulting from the heating process
We found that the protein expression levels of PLA2-3, receptor-interacting serine/threonine-protein kinase (RIPK)-1, receptor-interacting proteins-3 (RIPK-3), P-mixed lineage kinase domain-like protein (MLKL), tumor necrosis factor α (TNF-α), and IL-1β in the liver tissue of mice treated with furosine increased (Figure 3A,D) in a dose-dependent manner, suggesting that furosine could upregulate the expression of PLA2-3 and activate the necroptosis pathway
We found that LPC (18:0) upregulated the protein expression of receptor-interacting proteins-1 (RIPK-1), RIPK-3, P-MLKL, TNF-α, and IL-1β (Figure 3C,F) compared with the PLA2-3 siRNA group, without affecting the level of PLA2-3 that remained much lower than the control level, confirming that PLA2-3 was the upstream regulator of LPC (18:0)
Summary
The Maillard reaction is one of the most important reactions resulting from the heating process. As one of the typical MRPs [1], furosine (C12H18N2O4, 254.28 g/mol) was identified as ε-N-(2-furoylmethyl)-l-lysine in 1968 [2,3]; it is broadly found in a variety of foods including dairy products, cereals, honey, bakery products, etc., and its content is directly related to the degree of heating treatment and to the storage time [4]. What is the toxicity mechanism of furosine? There are very few available data evaluating the overall toxicity and metabolites of furosine, though it is urgent to assess furosine’s safety and control its production in food. The overall toxicity of furosine was evaluated. The toxicological mechanism and specific metabolites of furosine in living organisms remain unknown
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