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Our previous observation revealed that probucol, a well known cholesterol-lowering drug, can improve impaired catabolism of plasma triglyceride in streptozotocin-diabetic rats without reducing plasma glucose. The present sttudy was conducted using Triton WR1339 and endogenously radiolabled lipoproteins in order to examine the mechanisms whereby the drug can stimulate triglyceride removal from the circulation in rats independent of glucose metabolism.Methods: The short- and long-term effects of probucol on triglyceride turnover were examined in rats. Male Wistar rats received a diet containing probucol (1%) for 2 weeks and 4 months. Triglyceride turnover was estimated in rats using Triton WR1339.After 2 weeks of probucol administration, triglyceride and cholesterol concentrations in plasma and in the very-low-density lipoprotein (VLDL) fraction were suppressed slightly but significantly in the probucol-administered rats compared with standard chow-fed control rats. However, triglyceride secretion rates were similar in the two groups. Probucol-administered rats showed markedly suppressed triglyceride concentration in plasma and the VLDL fraction compared with chow-fed control rats after 4 months of administration. However, triglyceride secretion rate was significantly increased in rats given probucol. The radioisotope experiment revealed that probucol-administered rats can remove VLDLs (lipoproteins either from probucol-administered or control rats) from their system faster than normal rats and that probucol-containing VLDL can be removed from the circulation of both groups of rats more rapidly than normal VLDL. Therefore, probucol-administered rats as well as probucol-containing VLDL (lipoprotein from probucol-administered rats) are responsible for accelerated catabolism of VLDL-triglyceride.No significant differences in the lipid composition of newly-secreted VLDL particles between control rats and those given probucol were noted after Triton injection. The precise mechanism behind increased triglyceride secretion rate in rats after long-term administration of probucol is not known. However, we concluded from the present data that long-term administration of probucol results in markedly accelerated VLDL-triglyceride turnover without affecting lipid composition of newly secreted VLDL particles in normal rats.