In this study, we investigated the effect of atorvastatin, an HMG-CoA reductase inhibitor and CL277082, an ACAT inhibitor, on apolipoprotein B48 synthesis, degradation and secretion in transformed human intestinal enterocytes (CaCo2 cells). Cells were incubated with atorvastatin or CL277082 in the absence or presence of sterol containing media and pulsed with [S35]-methionine and chased with unlabelled methionine. Concomitantly, the effect of atorvastatin and CL277082 on the relative amount of apoB48 protein in cells and media was also quantified by western blotting using an apoB antibody and enhanced chemiluminescence. Suppression of cholesterol synthesis with atorvastatin did not attenuate the production or secretion of apoB48 from CaCo2 cells under basal conditions. On the other hand, suppression of cholesterol biosynthesis with atorvastatin under stimulatory conditions accelerated the degradation of apoB48 in cells without affecting its synthesis or secretion. There was no effect of exogenous sterols on apoB48 secretion. Taken together, neither endogenous nor exogenous cholesterol appears to acutely modulate apoB48 secretion from intestinal cells. In contrast, inhibition of cholesterol esterification with ACAT inhibitor significantly attenuated apoB48 secretion under basal and stimulatory conditions by a mechanism which enhanced apoB48 degradation. Collectively, our results suggest that in CaCo2 cells, newly synthesized cholesterol ester may be an immediate regulator apoB48 secretion.

01 Nov 2001·Journal of Pharmaceutical Sciences

Influence of membrane partitioning on inhibitors of membrane-bound enzymes

Article

Author: Katherine L. Hamelehle ; Reynold Homan

Membrane-water partitioning of inhibitors of acyl-coenzyme A:cholesterol acyltransferase (ACAT) governs the concentration of inhibitor that ACAT is exposed to and determines the corresponding extent of cholesterol esterification inhibition. Partitioning of the ACAT inhibitors CI-976, CL 277,082, and SaH 58-035 into rat liver microsomes containing ACAT was detected by shifts in the level of inhibition that were independent of inhibitor concentration but inversely dependent on microsome membrane concentration. The equilibrium distribution of the ACAT inhibitors between aqueous and membrane phases was derived directly from these data by application of a previously described method of linear analysis. The accuracy of membrane partitioning analysis based on kinetic data was verified for CI-976 by direct measurements of [14C]CI-976 partitioning into phospholipid membranes. The results show that the ACAT inhibitors are highly partitioned into membranes by factors exceeding 1 x 10(6). This result is consistent with the far greater influence of membrane content over aqueous volume on inhibitor activity. The results demonstrate that the size of the membrane phase in aqueous suspension must be taken into account to obtain accurate and reproducible kinetic characterizations of membrane-active molecules. Analyses of the membrane-dependent shifts in activity can be used to calculate the membrane-water partitioning coefficient of membrane-active molecules such as ACAT inhibitors.

01 Mar 1998·MetabolismQ1 · MEDICINE

Inhibition of acyl coenzyme A: Cholesterol acyltransferase blocks esterification but not uptake of cholesterol in Caco-2 cells

Q1 · MEDICINE

Article

Author: Jeff L. Ellsworth ; Jacqueline R. Starr

The effects of cholesterol esterase (CEase) and acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on the uptake and esterification of cholesterol in Caco-2 cells were examined. CEase increased the uptake of [3H]cholesterol from bile salt mixed-micelles by 2.5- to 3.0-fold and its esterification by greater than 25-fold. Inhibition of cellular ACAT activity with CL277082 or CP113818 had little or no effect on cholesterol uptake measured in the presence or absence of CEase. The subsequent esterification of [3H]cholesterol was reduced greater than 90% by each ACAT inhibitor. Similar results were obtained in cells in which ACAT activity was induced by preincubation either with 25-hydroxycholesterol and mevalonic acid or with CEase and bile salt mixed-micelles containing 100 micromol/L cholesterol. Neither ACAT inhibitor had an effect on CEase-mediated synthesis or hydrolysis of cholesteryl oleate in vitro. Thus, the uptake of cholesterol from bile salt mixed-micelles in the presence or absence of CEase was not regulated by the level of cellular ACAT expression. The subsequent esterification of exogenous sterol was not due to CEase, but was completely dependent on ACAT activity. The dissociation of cholesterol uptake from ACAT activity suggests that the factors controlling the transfer of sterol from extracellular media to the cell are different from the factors regulating the cellular level of cholesterol esterification.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 3	US	Wyeth Ltd. (India)	-
Hyperlipidemias	Phase 1	-	Pfizer Inc.	-

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