S-8921, an ileal Na+/bile acid cotransporter inhibitor decreases serum cholesterol in hamsters

Hara, Shinji; Higaki, Junko; Higashino, Kenichi; Iwai, Mie; Takasu, Nobuo; Miyata, Kenji; Tonda, Kanya; Nagata, Kiyoshi; Goh, Yasumasa; Mizui, Takuji

doi:10.1016/s0024-3205(97)00242-7

Cited by 32 publications

(24 citation statements)

References 15 publications

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“…Therefore, it is desirable to develop a hypocholesterolemic agent that interrupts the reabsorption of bile acids, resulting in increased cholesterol catabolism at more reasonable therapeutic doses. Inhibitors of ASBT have been reported with IC 50 values in the micromolar range, and some of these have been shown to reduce total cholesterol in various animal models (20)(21)(22)(23)(24)(25). Development of potent agents that specifically inhibit intestinal uptake of bile acids by ASBT are likely to be more efficacious than the bile acid binding resins (26).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Bhat

Rapp

Beaudry

et al. 2003

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 99%

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Bhat

Rapp

Beaudry

et al. 2003

Journal of Lipid Research

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“…The strongest compound in this group is S 8921 6 , which is a mixed competitive and non-competitive ASBT inhibitor with an IC 50 value of 2.5 μM (Hara et al 1997;Tollefson et al 2000). In vivo studies with S 8921 were performed in hamsters, rats and rabbits and revealed an upregulation of the cholesterol 7α-hydroxylase and HMG-CoA reductase activities, an increase in the hepatic LDL-receptor expression concomitant with reduced plasma cholesterol levels (Higaki et al 1998;Ichihashi et al 1998).…”

Section: Pharmacological Inhibition Of the Asbtmentioning

confidence: 99%

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Geyer

Wilke

Petzinger

2006

Naunyn Schmied Arch Pharmacol

161

138

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The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

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“…19,20 The small proportion of the pool that escapes ileal reabsorption throughout the day is replaced by an equivalent amount of newly synthesized bile acid from the liver, thereby maintaining a constant pool size. 12,13 While pharmacological inhibition of ileal bile acid transport in cholesterol-fed hamsters has been shown to significantly lower their plasma LDLcholesterol levels, 21 the question of how this transport process is regulated in response to manipulations like fasting, or feeding bile acid or cholestyramine remains controversial. [22][23][24][25][26][27] This situation has resulted partly because of the widely different experimental approaches that have been used to study the problem.…”

mentioning

confidence: 99%

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

Turley¹,

Schwarz

Spady³

et al. 1998

Hepatology

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These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any genderrelated differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 mol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 mol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25.3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2.1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7␣-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 mol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels. (HEPATOLOGY 1998;28:1088-1094.)The central role that the liver plays in the maintenance of whole-body sterol balance and the regulation of plasma low-density lipoprotein (LDL)-cholesterol levels stems partly from its unique ability to convert cholesterol to bile acids, the excretion of which represents a major route for the elimination of cholesterol from the body.

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S-8921, an ileal Na+/bile acid cotransporter inhibitor decreases serum cholesterol in hamsters

Cited by 32 publications

References 15 publications

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

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