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Ursodeoxycholate conjugates protect against disruption of cholesterol-rich membranes by bile salts



Ursodeoxycholate conjugates protect against disruption of cholesterol-rich membranes by bile salts



Gastroenterology 106(5): 1333-1341



Background/Aims: Ursodeoxycholic acid attenuates hepatocellular injury in cholestatic disorders, possibly by counteracting membrane disruptive effects of endogenous bile salts. The possible physicochemical basis of this protective effect was explored by using model membranes composed of egg phosphatidylcholine and cholesterol. Methods: Large unilamellar vesicles containing trapped 3H inulin were prepared by extrusion and gel filtration. Vesicle disruption (release of trapped inulin) was quantified using rapid centrifugal ultrafiltration. Results: Disruption of membranes increased with bile salt concentration, hydrophobicity, and increasing ionic strength. Disruption decreased with a decreasing bile salt/phospholipid ratio or an increasing cholesterol/phospholipid ratio. Vesicle disruption by taurodeoxycholate (3-alpha,12-alpha-dihydroxy-5-beta-cholanoyl taurine) was reduced in a concentration-dependent manner by addition of tauroursodeoxycholate (3-alpha,7-beta-dihydroxy-5-beta-cholanoyl taurine) (TUDC) when the cholesterol/phospholipid ratio was gtoreq 0.5, but TUDC was not protective at a cholesterol/phospholipid ratio ltoreq 0.2. Glycoursodeoxycholate (3-alpha,7-beta-dihydroxy-5-beta-cholanoyl glycine) was somewhat less protective than TUDC, and unconjugated ursodeoxycholate (3-alpha,7-beta-dihydroxy-5-beta-cholanoate) (UDC) had little effect. Taurine conjugates of several other hydrophilic bile salts were also protective, but protection was not strictly proportional to hydrophilicity. Conclusions: Conjugates of UDC and other hydrophilic bile salts can reduce disruption of cholesterol-rich model membranes by more toxic bile salts via a purely physicochemical mechanism. UDC conjugates in vivo may protect the cholestatic liver by preventing bile salt disruption of the cholesterol-rich canalicular membrane.

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Accession: 009702041

Download citation: RISBibTeXText

PMID: 8174892

DOI: 10.1016/0016-5085(94)90027-2


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