MDL 29311 is an antioxidant that lowers plasma triglycerides and raises high density lipoprotein (HDL) cholesterol in rats. It lowers triglycerides in rats by enhancing the clearance of very low density lipoprotein (VLDL) by the liver (Sheetz, M. J., et al. 1994. Metabolism. 43: 232-240). In this paper, the possibility that MDL 29311 enhances VLDL clearance by altering the apolipoprotein (apo) content of lipoproteins is examined. Treatment of rats with 1% MDL 29311 in the diet for 7 days lowered plasma triglycerides and markedly increased total lipoprotein-associated apoE. The increase in apoE was confined to the HDL fraction; no increase in VLDL-associated apoE was detected. No apparent alterations in the amount of total lipoprotein-associated apoC were observed, although there was a decrease in VLDL-associated apoC-II and C-III-0. Consistent with this finding, the amount of 125I-labeled apoC transferred from HDL to VLDL in plasma from MDL 29311-treated rats was only 40% of the amount transferred in control plasma. Sepharose 6B gel filtration of mixtures of 125I-labeled apoC with increasing concentrations of MDL 29311 in the absence of plasma or lipid revealed that proportionally increasing amounts of the 125I-labeled apoC eluted in a high molecular weight (HMW) complex with MDL 29311. An HMW complex was not formed when MDL 29311 was mixed with 125I-labeled soybean trypsin inhibitor. The 125I-labeled apoC in the HMW complex bound to VLDL only 20% as well as uncomplexed 125I-labeled apoC. MDL 29311 also caused the dissociation of 125I-labeled apoC from VLDL at concentrations of MDL 29311 similar to those obtained in vivo. Other phenolic antioxidants related to MDL 29311 caused the formation of HMW 125I-labeled apoC-containing complexes to an extent proportional to their abilities to lower triglycerides in rats. These studies support the hypothesis that MDL 29311 lowers triglycerides in rats by interfering with apoC association with VLDL, thereby relieving the apoC-mediated inhibition of hepatic VLDL uptake.

1994-12-01·Lipids4区 · 医学

Interactions of MDL 29,311 and probucol metabolites with cholesteryl esters

4区 · 医学

Article

作者: Karen A. Hagaman ; Nick Brake ; Larry R. McLean

Abstract:

The hypothesis that the efficacy of hydrophobic antioxidants in animal models of atherogenesis may, in part, be related to physical effects on cholesteryl esters in cells was probed with analogs and metabolites of probucol. The interactions of an effectivebis‐thiomethane analog (MDL 29,311) and selected metabolites of probucol with cholesteryl oleate were examined by differential scanning calorimetry and polarized light microscopy. Like probucol, MDL 29,311 and the bisphenol metabolite decrease the liquid‐crystalline phase transition enthalpy of cholesteryl oleate with increasing concentrations. At 20 mol%, no transition is detectable. By contrast, the spiroquinone metabolite of probucol and the diphenoquinone metabolite common to both molecules have minimal effects on the liquid‐crystalline transitions of cholesteryl oleate. At 20 mol%, neither compound has as great an effect as 1 mol% MDL 29,311. Consistent with their effects on dry cholesteryl oleate, MDL 29,311 and the bisphenol metabolite convert lipid inclusions in cells supplemented with cholesterol to an isotropic physical state similar to that observed with probucol. The number of anisotropic inclusions in the cells decreases with increasing concentration in the medium in the range of 50 to 250 μg/mL. In cells fed with the spiroquinone or diphenoquinone metabolites, the lipid inclusions are liquid‐crystalline and resemble those observed with cholesterol‐fed controls. These data are interpreted in terms of a model in which hydrophobic antioxidants closely related to probucol disrupt the packing of cellular cholesteryl esters.

1994-02-01·Metabolism: clinical and experimental1区 · 医学

MDL 29311, an analog of probucol, decreases triglycerides in rats by increasing hepatic clearance of very-low-density lipoprotein

1区 · 医学

Article

作者: Roger L. Barnhart ; Matthew J. Sheetz ; Keith M. Robinson ; Richard L. Jackson

MDL 29311 is an analog of probucol that shares probucol's antioxidant and antiatherogenic properties. When fed to rats as a 1% dietary admixture, MDL 29311 decreased triglyceride levels by 65% without affecting total or high-density lipoprotein (HDL) cholesterol levels. Under the same conditions, probucol decreased triglyceride levels by 23% and total cholesterol levels by 29% (with a corresponding decrease in HDL cholesterol level). MDL 29311 treatment did not affect the rate of triglyceride entry into the plasma. However, MDL 29311-treated rats cleared in vivo-labeled very-low-density lipoprotein (VLDL)-associated [3H]-triglyceride ([3H]-VLDL) over threefold faster than control rats. This increase in clearance led to increased levels of [3H]-lipid in liver and decreased [3H]-lipid in fat, muscle, diaphragm, and kidney of MDL 29311-treated rats 1.5 to 2.0 minutes after injection of [3H]-VLDL. MDL 29311 treatment had no effect on lipoprotein lipase (LPL) or hepatic triglyceride lipase (H-TGL) activities, or on plasma apolipoprotein (apo) C-II-dependent LPL activation. Intravenously injected [3H]-VLDL was allowed to circulate in MDL 29311-treated or control rats for 1 minute, and the undiluted plasma was then perfused through rat livers in a recirculating system. The [3H] in MDL 29311 plasma was cleared threefold faster (t1/2, 1.3 v 3.8 minutes) than the [3H] in control plasma by control livers. Conversely, the [3H] in control plasma was cleared slowly (t1/2 = 3.5 minutes) by the livers of MDL 29311-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

100 项与 MDL-29311 相关的药物交易

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