HDL biology
Probucol still lowers HDL cholesterol in humans with complete CETP deficiency, disproving its CETP-dependent mechanism (Atherosclerosis 2003)
Original title: Modulation of HDL metabolism by probucol in complete cholesteryl ester transfer protein deficiency
Probucol had been postulated to boost reverse cholesterol transport by enhancing CETP activity, but its effect in the total absence of CETP was untested. In two patients with complete CETP deficiency, who at baseline had smaller LDL and larger HDL particles than controls, probucol (500 mg/day) decreased HDL-cholesterol and apoA-I by up to 22% and shrank HDL particle size, while LDL-cholesterol was unchanged in one patient and fell 47% in the other. Paraoxonase 1 activity per HDL-C, about 40% lower than matched controls at baseline, rose 30% during treatment, and LDL and HDL oxidation lag time more than doubled in both cases. This is the first demonstration that probucol lowers HDL-C even without any CETP activity, while still protecting lipoproteins against oxidative stress.
Original abstract
Probucol, an antioxidative and hypolipidemic agent, has been postulated to increase reverse cholesterol transport by enhancing cholesteryl ester transfer protein (CETP) activity. However, its clinical implication in CETP deficient patients has not been fully defined. To characterize the effects of probucol in the absence of CETP, we evaluated the changes in lipid profile, lipid peroxidation, and paraoxonase 1 (PON1) activity in two complete CETP deficient patients, caused by treatment with probucol. When the patients were not receiving probucol, low-density lipoprotein (LDL) particles were smaller and high-density lipoprotein (HDL) particles were larger in these patients than in controls. Treatment with probucol (500 mg/day) resulted in the decrease in the levels of HDL-C and apolipoprotein (apo) A-I up to 22%. The size of HDL particles became smaller. LDL cholesterol concentration did not change in one patient, while it decreased by 47% in the other. PON1 activity/HDL-C, which was about 40% lower in the patients before treatment than in controls with the matching PON1 genotype, increased by 30% during the treatment. Lag time for LDL and HDL in both cases became prolonged more than 1.8 times after administration of probucol. This study demonstrated for the first time that probucol reduces HDL-C even in humans with complete CETP deficiency. Probucol treatment in these patients was also associated with protection of lipoproteins against oxidative stress, suggesting a clinical benefit of this drug even in such a state.
HDL biologymechanismspharmacology
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.