Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient

Abstract

Advanced glycation of proteins and their attendant advanced glycation end products (AGEs) contribute to the complications associated with diabetes mellitus or uremia. Here we report a patient in whom the glyoxalase detoxification system of precursor reactive carbonyl compounds (RCOs) is implicated in the in vivo AGE formation. This 69-year-old lady had been on hemodialysis (HD) for 3 years and had suffered from recurrent cardiovascular complications despite the absence of risk factors. Plasma levels of pentosidine and carboxymethyllysine (CML) were markedly elevated as compared to other HD patients. Plasma level of RCO precursors for pentosidine and CML was also higher than in other HD patients. Further investigation disclosed a very low activity in red blood cells (RBC) of glyoxalase I, an enzyme essential for the detoxification of oxoaldehydes. The glycoxalase I protein level, assessed in RBC by immunoblot analysis with a specific antibody, was also markedly lower than that observed in HD patients and normal subjects. Nucleotide sequencing of the products of RT-PCR from the patient's mononuclear cells revealed no genetic mutation within the coding region of the glyoxalase I gene. Plasma d-lactate level, the final product resulting from the glyoxalase detoxification pathway, was also in the lower range of the values measured in the other HD patients and normal subjects. The plasma levels of various compounds known to generate AGE precursors as well as the surrogate markers for oxidative stress such as antioxidant enzymes and glutathione were all within the range observed in the other HD patients. These data suggest that the unusually high levels of AGEs in this patient implicates a deficient glyoxalase detoxification of carbonyl precursors.