Structure of advanced Maillard reaction products and their pathological role

In this article we review recent progress and controversies relating to three areas of the field of advanced glycosylation end-products (AGE). A controversy exists as to whether pyrraline, an AGE detectable by immunohistochemistry in kidneys from patients with renal failure, exists in vivo. Recent data from the authors' laboratory revealed that pyrraline is present in alkaline or protease digests from human skin and plasma. However, the amounts are very low and pyrraline was found to undergo further reactions to form an ether with itself (dipyrraline) as well as a thioether with cysteine. This high reactivity of pyrraline may explain the difficulty of quantitating it accurately in biological material. In contrast, the glycoxidation products carboxymethyllysine (CML) and pentosidine are stable, very resistant to acid hydrolysis and easy to quantitate. They are present in elevated concentrations in the extracellular matrix in diabetes mellitus and ageing. In the diabetic human lens, CML is not elevated, in contrast to pentosidine, suggesting a different mechanism of formation. Recent data in diabetic dogs have shown that pentosidine is elevated only in lenses from poorly controlled dogs, in contrast to LM-1, a fluorophore thought to arise from ascorbate. Further studies are needed to clarify the intracellular mechanism of glycoxidation. The greatest concentrations of AGEs and glycoxidation products are found in patients with end-stage renal disease, and they are almost completely normalized by renal transplantation. Comparison of peritoneal dialysis (PD) with haemodialysis (HD) showed that PD is associated with lower plasma protein pentosidine, possibly due to selective transport of pentosidine-rich protein across the peritoneal wall. Fractionation of plasma proteins from ESRD patients by size showed that 90% of pentosidine is linked to HMW protein and 1-2% is in free form. The mechanism of accelerated glycoxidation in ESRD is still not understood.