Comparison of pharmacokinetics between highly and mildly modified AGE proteins in mice

We previously demonstrated that RAW 264.7 cells (murine macrophage cell line) recognize highly modified advanced glycation end products (AGE)-bovine serum albumin (BSA) (high-AGE-BSA), which was prepared by incubating BSA with 1600 mmol/L glucose for 40 weeks. In the present study, we prepared mildly modified AGE-BSA (mild-AGE-BSA) and conducted an endocytic uptake study using human monocyte-derived macrophages and Chinese hamster ovary cells which overexpressed such scavenger receptors as CD36, SR-BI (scavenger receptor class B type-I), and LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1). Although high-AGE-BSA was significantly recognized by these cells, mild-AGE-BSA did not show any ligand activity to these cells. Furthermore, when 111 In-labeled mild- or high-AGE-BSA was injected into the tail vein of male ddY mice, 111 In-high-AGE-BSA was rapidly cleared from the circulation, with about 80% of the injected 111 In-high-AGE-BSA being eliminated within 5 min. In contrast, the clearance rate of 111 In-mild-AGE-BSA was very slow, similar to the 111 In-native BSA. Taken together, our results indicate that the ligand activity of AGE-BSA to scavenger receptors and those pharmacokinetic properties depend on their rate of modification by AGEs.