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Chemical Compound Review:

AC1NSXLN 4-[(5R,8S,10S,13R)-3-hydroxy- 10,13...

Synonyms:

Vu, D.D. et al., Adachi, R. et al., Das, J.B. et al., Janciauskiene, S. et al., Makino, T. et al., et al.

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Disease relevance of LITHOCHOLIC ACID

LCA was without effect on the induction of either hepatocellular carcinomas or cholangiocarcinomas [1].
Both DCA, at a dose of 0.1%, and LCA significantly enhanced the induction of pancreas carcinomas [1].
These data associate an increase in biliary LCA with the emergence of cholestasis during TPN in rabbits [2].

High impact information on LITHOCHOLIC ACID

Treatment of mice with VD3 or LCA demonstrated in vivo modulation of the Mrp3 gene in colon but not in the liver [3].
We propose a docking model for LCA binding to VDR that is supported by mutagenesis data [4].
To identify structural determinants required for VDR activation by 1alpha,25(OH)2D3 and LCA, we generated VDR mutants predicted to modulate ligand response based on sequence homology to pregnane X receptor, another bile acid-responsive nuclear receptor [4].
In both vitamin D response element activation and mammalian two-hybrid assays, we found that VDR-S278V is activated by 1alpha,25(OH)2D3 but not by LCA, whereas VDR-S237M can respond to LCA but not to 1alpha,25(OH)2D3 [4].
At monolayer collapse, the molecular area of LCA was approximately 85 A(2) independent of pH, consistent with the steroid nucleus lying flat [5].

Chemical compound and disease context of LITHOCHOLIC ACID

To evaluate the role of lithocholic acid (LCA) in the etiology of parenteral nutrition-associated cholestasis (PN-AC), we studied (i) the changes in the percentage of biliary LCA and (ii) the emergence and resolution of cholestatic changes in the liver after total parenteral nutrition (TPN) and after 6 weeks of oral feeding following the TPN [2].

Biological context of LITHOCHOLIC ACID

Furthermore, LCA hydroxylation is thought to be a major detoxifying mechanism [6].

Anatomical context of LITHOCHOLIC ACID

An LCA% > or = 6 was associated with liver cell damage [2].
These data suggest that increased tight junction permeability and decreased BCM fluidity are important pathogenic steps in LCA-induced cholestasis [7].
At the end of the experiment (normal BF), 20% of the LCA injected was still in the liver but was present mainly in the cytosol [6].
At 60 min (maximal cholestasis), 30% of the LCA injected was secreted in bile, 20% was found in plasma while the other 50% was recovered in the liver and distributed mainly in plasma membranes, microsomes and cytosol [6].
These results suggest that: (i) LCA binding to plasma membranes and microsomes appeared to correlate with the development of cholestasis; (ii) LCA glucuronidation may initiate and/or contribute to LCA-induced cholestasis; and (iii) hydroxylation predominates during recovery from cholestasis [6].

Associations of LITHOCHOLIC ACID with other chemical compounds

Recently, secondary bile acids such as lithocholic acid (LCA) were identified as endogenous VDR agonists [4].

Gene context of LITHOCHOLIC ACID

Studies of the AAT in complex with LA by using far-UV spectra circular dichroism and fluorescence measurements indicated an increase of beta-structure of AAT and pronounced changes in surroundings of the chromophores [8].

References

Effects of phenobarbital and secondary bile acids on liver, gallbladder, and pancreas carcinogenesis initiated by N-nitrosobis (2-hydroxypropyl)amine in hamsters. Makino, T., Obara, T., Ura, H., Kinugasa, T., Kobayashi, H., Takahashi, S., Konishi, Y. J. Natl. Cancer Inst. (1986) [Pubmed]
Biliary lithocholate and cholestasis during and after total parenteral nutrition: an experimental study. Das, J.B., Uzoaru, I.L., Ansari, G.G. Proc. Soc. Exp. Biol. Med. (1995) [Pubmed]
Vitamin D receptor-dependent regulation of colon multidrug resistance-associated protein 3 gene expression by bile acids. McCarthy, T.C., Li, X., Sinal, C.J. J. Biol. Chem. (2005) [Pubmed]
Structural determinants for vitamin D receptor response to endocrine and xenobiotic signals. Adachi, R., Shulman, A.I., Yamamoto, K., Shimomura, I., Yamada, S., Mangelsdorf, D.J., Makishima, M. Mol. Endocrinol. (2004) [Pubmed]
Spread monomolecular films of monohydroxy bile acids and their salts: influence of hydroxyl position, bulk pH, and association with phosphatidylcholine. Leonard, M.R., Bogle, M.A., Carey, M.C., Donovan, J.M. Biochemistry (2000) [Pubmed]
Pathogenesis of lithocholate-induced intrahepatic cholestasis: role of glucuronidation and hydroxylation of lithocholate. Vu, D.D., Tuchweber, B., Plaa, G.L., Yousef, I.M. Biochim. Biophys. Acta (1992) [Pubmed]
Tight junction permeability and liver plasma membrane fluidity in lithocholate-induced cholestasis. Vu, D.D., Tuchweber, B., Raymond, P., Yousef, I.M. Exp. Mol. Pathol. (1992) [Pubmed]
In vitro amyloid fibril formation from alpha 1-antitrypsin. Janciauskiene, S., Carlemalm, E., Eriksson, S. Biol. Chem. Hoppe-Seyler (1995) [Pubmed]

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