The effects of gliclazide and other sulfonylureas on low-density lipoprotein oxidation in vitro.
Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.
O'Brien
R C
RC
Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Luo
M
M
D000284:Administration, Oral; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D005907:Gliclazide / Q000008:administration & dosage / Q000494:pharmacology*; D005913:Glipizide / Q000008:administration & dosage / Q000494:pharmacology; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014044:Tolbutamide / Q000008:administration & dosage / Q000494:pharmacology
D000975:Antioxidants; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D013453:Sulfonylurea Compounds; D014044:Tolbutamide; D005907:Gliclazide; D001205:Ascorbic Acid; D005905:Glyburide; D005913:Glipizide