Abstract
Inhibition of the ileal bile acid active transport system, previously shown to be mechanism underlying the hypocholesterolemic activity of 2164U90 in rodents, was further characterized in isolated intestinal preparations from three species. 2164U90 inhibited sodium-dependent transport of taurocholic acid by Caco-2 cells and by monkey and human ileal brush border membrane vesicles in a concentration-dependent manner with IC50s of 7 microM, 5 microM, and 2 microM, respectively. In rat ileal brush border membrane vesicles, 2164U90 was a competitive inhibitor of sodium-dependent taurocholic acid uptake with an estimated Ki of 1.8 +/- 0.2 microM. In anesthetized rats, 5 microM 2164U90 placed in the isolated distal ileum with 3 mM [3H]taurocholic acid decreased ileal uptake, transport into the bile, and transport rate of taurocholic acid by 31-35%. Stereospecificity of inhibition by 2164U90 was demonstrated by the relative inactivity of three other possible stereoisomers in rat ileal sacs and brush border membrane vesicles. 2164U90 did not inhibit sodium-dependent glucose transport by monkey jejunal brush border membrane vesicles, indicating that 2164U90 may be specific for the bile acid transporter. These results suggest that 2164U90 is a potent, selective, stereospecific, competitive inhibitor of the sodium-dependent bile acid transporter in the ileal mucosal cell brush border membrane.
Highlights
Inhibition of the ileal bile acid active transport system, previously shown to be mechanism underlying the hypocholesterolemic activity of 2164U90 in rodents, was further characterizedin isolated intestinal preparations from three species. 2164U90 inhibited sodium-dependent transport of taurocholic acid by Caco-2 cells and by monkey and human ileal brush border membrane vesicles in a concentration-dependent manner with IC5,s of 7 pM, 5 p M, and 2 pM, respectively
In a controlled clinical trial, this surgery produced a sustained lowering of plasma LDL cholesterol (38% after 5 years), a significant decrease (35% lower incidence) in the combined end point of death due to coronary heart disease and nonfatal myocardial infarction, and a significant slowing of the progression of Abbreviations: LDL, low density lipoprotein; VLDL, very low density lipoprotein; TC, taurocholic acid; BBMV, brush border membrane vesicles; RSS, residual sums of squares; BLM, basolateral membrane
The effects of 2164U90 and 2163U90 on the sodiumdependent transport of TC by Caco-2 cells are summarized in Table 2. 2164U90 decreased the active transport of TC in a concentration-dependent manner with an IC5o of 7 pM. 2163U90 at 10 and 30 pM had no significant effect on TC active transport by Caco-2 cells
Summary
Inhibition of the ileal bile acid active transport system, previously shown to be mechanism underlying the hypocholesterolemic activity of 2164U90 in rodents, was further characterizedin isolated intestinal preparations from three species. 2164U90 inhibited sodium-dependent transport of taurocholic acid by Caco-2 cells and by monkey and human ileal brush border membrane vesicles in a concentration-dependent manner with IC5,,s of 7 pM, 5 p M , and 2 pM, respectively. Photoaffinity labeling studies in rabbit [7] and rat [8, 9] ileal brush border membranes with photoreactive taurocholic acid derivatives, and expression cloning studies of a cDNA from hamster ileum (lo), have identified integral membrane proteins that exhibit characteristics of the sodium-dependent bile acid transporter. This active transport system in the distal ileum is generally accepted to be the major route of bile acid reabsorption in humans and other animals [11,12,13,14,15,16]. In a controlled clinical trial, this surgery produced a sustained lowering of plasma LDL cholesterol (38% after 5 years), a significant decrease (35% lower incidence) in the combined end point of death due to coronary heart disease and nonfatal myocardial infarction, and a significant slowing of the progression of Abbreviations: LDL, low density lipoprotein; VLDL, very low density lipoprotein; TC, taurocholic acid; BBMV, brush border membrane vesicles; RSS, residual sums of squares; BLM, basolateral membrane
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