Effect of uric acid and chemical analogues on oxidation of human low density lipoprotein in vitro.
Oxidative modification of low density lipoprotein (LDL) is implicated in the early development of atherosclerosis. In the present study, attention has been focused toward the potential protective effects of uric acid and purine-based chemical analogues in copper-promoted oxidative changes to human LDL in vitro. Between 5-100 mumol/l uric acid protected LDL from oxidative degradation in a concentration dependent manner. However, 5 mumol/l were not capable of inhibiting the consumption of LDLs natural antioxidative components, alpha-tocopherol and beta-carotene, but led to a more than two-fold prolongation, up to 3 h, of the lag phase before onset of polyunsaturated acid (PUFA) oxidation. 100 mumol/l uric acid, which is still below the human serum level of 300 mumol/l, reduced consumption of alpha-tocopherol and beta-carotene by about 50% and largely suppressed PUFA oxidation for up to 4 h. A more lipophilic series of methyl analogues of uric acid exhibited less activity. Neither 1,3-dimethyl uric acid, nor the 1,3,7- or 1,7- or 3,7-methylated compounds, all at 100 mumol/l, exceeded the antioxidative potential of 10 mumol/l uric acid. At concentrations up to 100 mumol/l xanthine and its analogues lacked virtually any protective effects toward the LDL constituents. In conclusion, the present study indicates that uric acid at concentrations similar to its physiological levels, and also related analogues are able to suppress oxidative degradation of LDL components. In view of the various mechanisms underlying atherogenesis in vivo, the protective effect in terms of modulating redox reactions and oxidative events in the blood or at the arterial wall appears of potential importance.
Schlotte
V
V
Hoechst Marion Roussel, Wiesbaden, Germany.
Sevanian
A
A
Hochstein
P
P
Weithmann
K U
KU
D000975:Antioxidants; D001095:Arachidonic Acids; D002788:Cholesterol Esters / Q000378:metabolism; D003300:Copper / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010084:Oxidation-Reduction; D011687:Purines / Q000494:pharmacology; D014527:Uric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014810:Vitamin E / Q000378:metabolism; D019820:Xanthine / Q000494:pharmacology; D019207:beta Carotene / Q000378:metabolism
D000975:Antioxidants; D001095:Arachidonic Acids; D002788:Cholesterol Esters; D005231:Fatty Acids, Unsaturated; D008077:Lipoproteins, LDL; D011687:Purines; D019207:beta Carotene; D014810:Vitamin E; D019820:Xanthine; D014527:Uric Acid; C029382:cholesteryl arachidonate; D003300:Copper; C030985:purine