UNEXPECTED DOSE-RESPONSE OF COPPER CONCENTRATION ON LIPOPROTEIN OXIDATION IN SERUM - DISCOVERY OF A UNIQUE PEROXIDASE-LIKE ACTIVITY OF URATE ALBUMIN IN THE PRESENCE OF HIGH COPPER CONCENTRATIONS/

Oxidative modification of low-density lipoprotein (LDL) may be an impo rtant factor in atherogenesis. The susceptibility of LDL to oxidation is usually determined in isolation by exposing LDL to oxidative stress induced by Cu ions or a free radical initiator, In these cases oxidat ion is carried out in the absence of water-soluble vitamins or serum p roteins that may be present at the site of oxidation in vivo, We have examined the Cu2+-induced oxidation of lipoproteins in diluted serum. When oxidizing isolated LDL, there is a decrease in lag time with incr easing concentration of Cu2+ until a minimum ''lag time'' is reached a t a Cu:LDL ratio of about 50:1. In serum, we have shown an initial dec rease in ''lag time'' with increasing Cu concentration up to 12.5 mu M . However, with higher Cu concentrations ''lag time'' to oxidation inc reases, contrary to expectation, until a maximum is reached at about 5 0 mu M Cu. This dose response observed for Cu oxidation of diluted ser um was highly reproducible in a number of individual subjects, When se rum was gel-filtered to remove low molecular weight compounds, the res ulting filtrate behaved the same as isolated LDL. Uric acid was found to be an important component of the low molecular weight fraction resp onsible for the paradoxical effect of Cu concentration on serum oxidat ion. The same paradoxical effect was found when isolated LDL was incub ated with uric acid in the presence of human serum albumin (HSA) and C u. The incubation of HSA with reducing agents such as uric acid or bil irubin in the presence of high Cu concentrations, produces a ''peroxid ase-like'' activity, capable of breaking down hydrogen peroxide as wel l as lipid hydroperoxides. The decomposition of lipid peroxides is a l ikely explanation for the longer serum oxidation lag times seen at hig her Cu concentrations. Our study highlights the possible importance of interactions between uric acid and serum proteins in the presence of high metal ion concentrations. (C) 1997 Elsevier Science Inc.