Long-term intake of the reactive metabolite methylglyoxal is not toxic in mice

Reactive carbonyls, including methylglyoxal (MG), are considered toxic compounds in foodstuffs because they irreversibly modify proteins and produce advanced glycation end products (AGEs). Therefore, we studied the long-term effect of increased MG intake in mature adult mice. Six-month-old C57BL/6N mice received MG by drinking water (2.5 mg/ml; i.e., 200-300 mg/kg BW/d) until death. This treatment caused an immediate strong increase in urine MG and a delayed moderate increase in plasma MG. At 24 months of age, mice administered MG showed no changes in the blood and tissue activity of glyoxalase-1 (Glo1), an intracellular MG-detoxifying enzyme; no signs of renal insufficiency and diabetes, including unchanged AGE modifications of plasma and vessel proteins; reduced tumour incidence; and slightly increased survival. Mice simultaneously deficient in the receptor for AGEs (RAGE) and overexpressing Glo1 exhibited higher basal plasma MG levels and did generally not respond to long-term MG intake. In vitro experiments supported the minor relevance of Glo1 in the detoxification of circulating MG but the important role of plasma albumin as an MG scavenger. In conclusion, the detoxification of dietary MG through renal excretion and further mechanisms largely prevents the toxicity of MG and possibly other food-derived reactive carbonyls in mature adults.