24-norUrsodeoxycholic acid

[Guest guest]

http://www.ncbi.nlm.nih.gov/pubmed/16472600

Hi,

Does anybody know anything about this or if it is being sold ?

Marna

[Guest guest]

Hi Marna;

As far as I know, the only group actively working on 24-

norUrsodeoxycholic acid is Dr. Trauner (in Austria) and his

collaborators (in different countries), mostly in animal models. I do

not know whether Dr. Trauner and colleagues have convinced a

pharmaceutical company to manufacture it yet. The person who first

synthesized it was Dr. Alan Hofmann (University of California, San

Diego) and he is one of Dr. Trauner's collaborators, and is presumably

the person providing this compound for their research?

Dr. Trauner and collaborators presented 3 papers at the " Falk Symposium

165, XX International Bile Acid Meeting, Bile Acid Biology and

Therapeutic Actions; June 13-14, 2008; Hotel Okura, Amsterdam, The

Netherlands " all dealing with their animal model work. The abstracts of

these papers are shown below:

_________________________________________

p. 54 of Abstract Booklet

Differential effects of ursodeoxycholic acid (UDCA) and sidechain-

shortened norUDCA in the treatment of fatty liver and atherosclerosis.

Fickert1, Tarek Moustafa1, Fuchsbichler2, Thierry Claudel1,

Emina Halilbasic1, Dagmar Kratky2, Kurt Zatloukal3, Helmut Denk3,

Trauner1

1Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Internal Medicine,

Medical University of Graz, Austria

2Institute of Molecular Biology and Biochemistry, Medical University of

Graz, Austria 3Institute for Pathology, Medical University of Graz,

Austria

Background: Beside their well established role in the regulation of

dietary lipid absorption and cholesterol homeostasis, bile acids may

also play a key role as endocrine signaling molecules that coordinate

hepatic lipid homeostasis through nuclear hormone receptors and thus

might represent a promising therapeutic treatment strategy for non-

alcoholic fatty liver disease (NAFLD) and arteriosclerosis.

However, ursodeoxycholic acid (UDCA), did not improve non-alcoholic

steatohepatitis (NASH) in humans (Lindor et al. Hepatology 2004) and

more effective therapies are needed. Moreover, UDCA has never has been

tested in models of atherosclerosis despite being known to reduce LDL-

cholesterol (LDL-C). We therefore aimed to explore the potential

therapeutic mechanisms of UDCA and its side chain-shortened homologue

norUDCA on NAFLD and arteriosclerosis in Western-diet fed ApoE-/- mice.

Methods: ApoE-/- mice were fed Western diet for 8 weeks (Co). Treatment

groups received either 0.5% UDCA or norUDCA in addition to Western diet

from week 4-8 (i.e. after development of hepatic steatosis and

athersosclersis). H&E and red oil staining, hepatic TG-levels,

expression of key genes in hepatic TG homeostasis, neutophil

infiltration and VCAM-1 expression, the degree of aortic (valve) plaque

formation, and serum lipid composition were compared.

Results: norUDCA significantly reduced hepatic triglyceride content,

induced FA oxidation (AOX mRNA expression), reduced TG synthesis (Lpin1

mRNA expression), neutrophil count, and VCAM expression. In addition,

norUDCA significantly reduced aortic plaques surface area and aortic

staining for macrophage marker F4/80. Interestingly, while UDCA

treatment significantly reduced total serum cholesterol and

triglyceride levels in ApoE-/- mice, norUDCA had no effect on both

parameters. However, FPLC-analysis clearly demonstrated an increase of

cholesterol and phospholipids in the HDL-fraction in norUDCA treated

animals when compared to Co. Moreover, norUDCA but not UDCA restored

Cyp7a1 expression in Western-diet fed animals.

Conclusions: norUDCA is superior to UDCA in the treatment of NAFLD and

arteriosclerosis in Western chow-fed ApoE-/- mice and these effects are

independent of total serum cholesterol and triglyceride levels. Due to

its multiple effects on lipoprotein composition, foam cell formation,

and hepatic lipid metabolism side-chain homologues of UDCA may

represent promising drugs to treat NAFLD and arteriosclerosis.

_________________________________________

p. 55 of Abstract Booklet

Side-chain-modification critically determines the physiologic and

therapeutic properties of 24-nor-ursodeoxycholic acid in the treatment

of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice and isolated

bile duct units.

Emina Halilbasic1, Fickert1, Romina Foirotto2 , Hanns Ulrich

Marschall3, Tarek Moustafa1, Fuchsbichler4, Judith Gumhold1,

Dagmar Silbert1, Cord Langner4, Uday Maitra5, Helmut Denk4 ,

Strazzabosco2, Trauner1

1Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Medicine, Medical

University Graz, Austria

2Section of Digestive Diseases, Department of Internal Medicine, School

of Medicine, Yale University, New Haven, USA

3Karolinska University Hospital Huddinge, Stockholm, Sweden

4Institute of Pathology, Medical University Graz, Austria

5Department of Organic Chemistry, Indian Institute of Science,

Bangalore, India

Background and aim: Nor-ursodeoxycholic acid (norUDCA) reverses

sclerosing cholangitis and biliary fibrosis in multidrug resistance

gene 2 knock-out (Mdr2-/-) mice. This may be critically related to the

relative conjugation resistance of norUDCA undergoing cholehepatic

shunting and inducing bicarbonate-rich hypercholeresis. To test this

hypothesis we compared the effects of norUDCA, its taurine conjugate

T-norUDCA, and further side chain shortened bis-norUDCA in Mdr2-/- mice

and isolated mouse bile duct units (IBDU).

Material and methods: 8 weeks-old Mdr2-/- mice were fed a standard chow

or a diet containing norUDCA, T-norUDCA or bis-norUDCA for 4 weeks.

Liver histology, serum liver enzymes, bile flow, markers of liver

fibrosis as well as mRNA expression of key detoxification and transport

systems were compared. Potential choleretic mechanisms in

cholangiocytes were addressed in IBDU in bicarbonate containing

and free medium.

Results: NorUDCA but not T-norUDCA, significantly reduced ALT/AP levels

and improved liver histology. In contrast, bis-norUDCA even

deteriorated the cholestatic phenotype. NorUDCA and bis-norUDCA

stimulated the expression of basolateral bile acid efflux pump Mrp4.

Induction of bile acid biotransformation enzymes (Cyp2b10 and Sult2a1)

was observed after norUDCA and bis-norUDCA treatment. Biliary

bicarbonate-output was 2-fold higher in norUDCA compared to T-norUDCA-

treated animals. NorUDCA stimulated bile secretion in IBDU more

potently than tauronorUDCA, effects which were partially bicarbonate-

dependent.

Summary and conclusion: NorUDCA is superior to its homologues in the

reduction of liver injury, ductular proliferation and periductal

fibrosis in Mdr2-/- mice, suggesting bicarbonate rich hypercholeresis

and cholehepatic shunting as its key mechanisms of action.

_________________________________________

p. 56 of Abstract Booklet

Role of side chain amidation for the anticholestatic action of norUDCA

in rat liver.

Silvia Maitz1,2, Ralf Wimmer1, Christian Rust1, Gerald U. Denk1, Pietro

Invernizzi2, Sacha Ferdinandusse3, J. Wanders3,

Fuchsbichler4, Fickert4, Trauner4, Alan F. Hofmann5,

Ulrich Beuers1,3

1Department of Medicine II, Klinikum Großhadern, University of Munich,

Germany

2Division of Internal Medicine and Liver Unit, San Paolo School of

Medicine,University of Milan, Italy

3Department of Gastroenterology & Hepatology, AMC, University of

Amsterdam, The Netherlands

4Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Medicine and Department

of Pathology, Medical University, Graz, Austria

5Division of Gastroenterology, Department of Medicine, University of

California, San Diego, CA, USA

Background and aim: The impact of taurine conjugation for the

anticholestatic effect of ursodeoxycholic acid (UDCA) and its taurine

conjugate (TUDCA) is unclear (Nature CP Gastr Hepat 2006; 3).

Norursodeoxycholic acid (norUDCA) exerts therapeutic effects superior

to UDCA in Mdr2/Abcb4 knockout mice (Mdr2-/-) that develop chronic

progressive sclerosing cholangitis (Gastroenterology 2006; 130:

465). In contrast to UDCA, norUDCA is poorly conjugated by rat and human

hepatocytes (Hepatology 2005; 42: 1319). Taurolithocholic acid (TLCA)-

induced cholestasis represents a well-established experimental model of

hepatocellular cholestasis. The aim of the present study was to compare

the effect of norUDCA and its taurine conjugate (TnorUDCA) on bile

formation and liver cell injury in TLCA-induced cholestasis of perfused

rat livers.

Methods: The effect of norUDCA and TnorUDCA (25 umol/l, each) on bile

flow and biliary secretion of the Mrp2 (Abcc2) substrate, 1,2-

dinitrophenyl-S-glutathione (GSDNP), was studied in presence or absence

of TLCA (10 umol/l) in isolated perfused rat livers (JBC 2003; 278:

17810). Bile acid administration was started after 45 min,

and 1-chloro-2,4-dinitrobenzene (CDNB, 30 umol/l), the precursor of GS-

DNP, was administered from min 65 to 75. Bile secretion was determined

gravimetrically, GSDNP secretion fluorometrically, biliary bile salt

composition by tandem mass spectrometry, and liver cell apoptosis by an

immunohistochemical approach (caspase 3, cytokeratin 18 staining).

Statistics: ANOVA with Tukey's post-hoc test.

Results: TnorUDCA and norUDCA stimulated bile flow in control livers,

but did not affect GS-DNP secretion. TnorUDCA, but not norUDCA,

reversed TLCA-induced impairment of bile flow and, in part, GS-DNP

secretion. TnorUDCA and norUDCA did not significantly affect TLCA-

induced apoptosis. TnorUDCA was detected at millimolar levels in bile

of livers treated with TLCA + TnorUDCA for 20 min, but not at relevant

levels (< 0.1 mmol/l) in those treated with norUDCA.

Conclusions: Taurine conjugation is essential for the anticholestatic

action of norUDCA in cholestasis induced by TLCA in perfused rat liver.

_________________________________________

I think this is the most recent published information on 24-

norUrsodeoxycholic acid. As far as I am aware it has not yet been

tested for its efficacy in human PSC in clinical trials, and it is not

yet sold as a drug for treatment of human cholestatic diseases.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> http://www.ncbi.nlm.nih.gov/pubmed/16472600

>

> Hi,

>

> Does anybody know anything about this or if it is being sold ?

>

> Marna

>

[Guest guest]

Hi Marna;

As far as I know, the only group actively working on 24-

norUrsodeoxycholic acid is Dr. Trauner (in Austria) and his

collaborators (in different countries), mostly in animal models. I do

not know whether Dr. Trauner and colleagues have convinced a

pharmaceutical company to manufacture it yet. The person who first

synthesized it was Dr. Alan Hofmann (University of California, San

Diego) and he is one of Dr. Trauner's collaborators, and is presumably

the person providing this compound for their research?

Dr. Trauner and collaborators presented 3 papers at the " Falk Symposium

165, XX International Bile Acid Meeting, Bile Acid Biology and

Therapeutic Actions; June 13-14, 2008; Hotel Okura, Amsterdam, The

Netherlands " all dealing with their animal model work. The abstracts of

these papers are shown below:

_________________________________________

p. 54 of Abstract Booklet

Differential effects of ursodeoxycholic acid (UDCA) and sidechain-

shortened norUDCA in the treatment of fatty liver and atherosclerosis.

Fickert1, Tarek Moustafa1, Fuchsbichler2, Thierry Claudel1,

Emina Halilbasic1, Dagmar Kratky2, Kurt Zatloukal3, Helmut Denk3,

Trauner1

1Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Internal Medicine,

Medical University of Graz, Austria

2Institute of Molecular Biology and Biochemistry, Medical University of

Graz, Austria 3Institute for Pathology, Medical University of Graz,

Austria

Background: Beside their well established role in the regulation of

dietary lipid absorption and cholesterol homeostasis, bile acids may

also play a key role as endocrine signaling molecules that coordinate

hepatic lipid homeostasis through nuclear hormone receptors and thus

might represent a promising therapeutic treatment strategy for non-

alcoholic fatty liver disease (NAFLD) and arteriosclerosis.

However, ursodeoxycholic acid (UDCA), did not improve non-alcoholic

steatohepatitis (NASH) in humans (Lindor et al. Hepatology 2004) and

more effective therapies are needed. Moreover, UDCA has never has been

tested in models of atherosclerosis despite being known to reduce LDL-

cholesterol (LDL-C). We therefore aimed to explore the potential

therapeutic mechanisms of UDCA and its side chain-shortened homologue

norUDCA on NAFLD and arteriosclerosis in Western-diet fed ApoE-/- mice.

Methods: ApoE-/- mice were fed Western diet for 8 weeks (Co). Treatment

groups received either 0.5% UDCA or norUDCA in addition to Western diet

from week 4-8 (i.e. after development of hepatic steatosis and

athersosclersis). H&E and red oil staining, hepatic TG-levels,

expression of key genes in hepatic TG homeostasis, neutophil

infiltration and VCAM-1 expression, the degree of aortic (valve) plaque

formation, and serum lipid composition were compared.

Results: norUDCA significantly reduced hepatic triglyceride content,

induced FA oxidation (AOX mRNA expression), reduced TG synthesis (Lpin1

mRNA expression), neutrophil count, and VCAM expression. In addition,

norUDCA significantly reduced aortic plaques surface area and aortic

staining for macrophage marker F4/80. Interestingly, while UDCA

treatment significantly reduced total serum cholesterol and

triglyceride levels in ApoE-/- mice, norUDCA had no effect on both

parameters. However, FPLC-analysis clearly demonstrated an increase of

cholesterol and phospholipids in the HDL-fraction in norUDCA treated

animals when compared to Co. Moreover, norUDCA but not UDCA restored

Cyp7a1 expression in Western-diet fed animals.

Conclusions: norUDCA is superior to UDCA in the treatment of NAFLD and

arteriosclerosis in Western chow-fed ApoE-/- mice and these effects are

independent of total serum cholesterol and triglyceride levels. Due to

its multiple effects on lipoprotein composition, foam cell formation,

and hepatic lipid metabolism side-chain homologues of UDCA may

represent promising drugs to treat NAFLD and arteriosclerosis.

_________________________________________

p. 55 of Abstract Booklet

Side-chain-modification critically determines the physiologic and

therapeutic properties of 24-nor-ursodeoxycholic acid in the treatment

of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice and isolated

bile duct units.

Emina Halilbasic1, Fickert1, Romina Foirotto2 , Hanns Ulrich

Marschall3, Tarek Moustafa1, Fuchsbichler4, Judith Gumhold1,

Dagmar Silbert1, Cord Langner4, Uday Maitra5, Helmut Denk4 ,

Strazzabosco2, Trauner1

1Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Medicine, Medical

University Graz, Austria

2Section of Digestive Diseases, Department of Internal Medicine, School

of Medicine, Yale University, New Haven, USA

3Karolinska University Hospital Huddinge, Stockholm, Sweden

4Institute of Pathology, Medical University Graz, Austria

5Department of Organic Chemistry, Indian Institute of Science,

Bangalore, India

Background and aim: Nor-ursodeoxycholic acid (norUDCA) reverses

sclerosing cholangitis and biliary fibrosis in multidrug resistance

gene 2 knock-out (Mdr2-/-) mice. This may be critically related to the

relative conjugation resistance of norUDCA undergoing cholehepatic

shunting and inducing bicarbonate-rich hypercholeresis. To test this

hypothesis we compared the effects of norUDCA, its taurine conjugate

T-norUDCA, and further side chain shortened bis-norUDCA in Mdr2-/- mice

and isolated mouse bile duct units (IBDU).

Material and methods: 8 weeks-old Mdr2-/- mice were fed a standard chow

or a diet containing norUDCA, T-norUDCA or bis-norUDCA for 4 weeks.

Liver histology, serum liver enzymes, bile flow, markers of liver

fibrosis as well as mRNA expression of key detoxification and transport

systems were compared. Potential choleretic mechanisms in

cholangiocytes were addressed in IBDU in bicarbonate containing

and free medium.

Results: NorUDCA but not T-norUDCA, significantly reduced ALT/AP levels

and improved liver histology. In contrast, bis-norUDCA even

deteriorated the cholestatic phenotype. NorUDCA and bis-norUDCA

stimulated the expression of basolateral bile acid efflux pump Mrp4.

Induction of bile acid biotransformation enzymes (Cyp2b10 and Sult2a1)

was observed after norUDCA and bis-norUDCA treatment. Biliary

bicarbonate-output was 2-fold higher in norUDCA compared to T-norUDCA-

treated animals. NorUDCA stimulated bile secretion in IBDU more

potently than tauronorUDCA, effects which were partially bicarbonate-

dependent.

Summary and conclusion: NorUDCA is superior to its homologues in the

reduction of liver injury, ductular proliferation and periductal

fibrosis in Mdr2-/- mice, suggesting bicarbonate rich hypercholeresis

and cholehepatic shunting as its key mechanisms of action.

_________________________________________

p. 56 of Abstract Booklet

Role of side chain amidation for the anticholestatic action of norUDCA

in rat liver.

Silvia Maitz1,2, Ralf Wimmer1, Christian Rust1, Gerald U. Denk1, Pietro

Invernizzi2, Sacha Ferdinandusse3, J. Wanders3,

Fuchsbichler4, Fickert4, Trauner4, Alan F. Hofmann5,

Ulrich Beuers1,3

1Department of Medicine II, Klinikum Großhadern, University of Munich,

Germany

2Division of Internal Medicine and Liver Unit, San Paolo School of

Medicine,University of Milan, Italy

3Department of Gastroenterology & Hepatology, AMC, University of

Amsterdam, The Netherlands

4Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Medicine and Department

of Pathology, Medical University, Graz, Austria

5Division of Gastroenterology, Department of Medicine, University of

California, San Diego, CA, USA

Background and aim: The impact of taurine conjugation for the

anticholestatic effect of ursodeoxycholic acid (UDCA) and its taurine

conjugate (TUDCA) is unclear (Nature CP Gastr Hepat 2006; 3).

Norursodeoxycholic acid (norUDCA) exerts therapeutic effects superior

to UDCA in Mdr2/Abcb4 knockout mice (Mdr2-/-) that develop chronic

progressive sclerosing cholangitis (Gastroenterology 2006; 130:

465). In contrast to UDCA, norUDCA is poorly conjugated by rat and human

hepatocytes (Hepatology 2005; 42: 1319). Taurolithocholic acid (TLCA)-

induced cholestasis represents a well-established experimental model of

hepatocellular cholestasis. The aim of the present study was to compare

the effect of norUDCA and its taurine conjugate (TnorUDCA) on bile

formation and liver cell injury in TLCA-induced cholestasis of perfused

rat livers.

Methods: The effect of norUDCA and TnorUDCA (25 umol/l, each) on bile

flow and biliary secretion of the Mrp2 (Abcc2) substrate, 1,2-

dinitrophenyl-S-glutathione (GSDNP), was studied in presence or absence

of TLCA (10 umol/l) in isolated perfused rat livers (JBC 2003; 278:

17810). Bile acid administration was started after 45 min,

and 1-chloro-2,4-dinitrobenzene (CDNB, 30 umol/l), the precursor of GS-

DNP, was administered from min 65 to 75. Bile secretion was determined

gravimetrically, GSDNP secretion fluorometrically, biliary bile salt

composition by tandem mass spectrometry, and liver cell apoptosis by an

immunohistochemical approach (caspase 3, cytokeratin 18 staining).

Statistics: ANOVA with Tukey's post-hoc test.

Results: TnorUDCA and norUDCA stimulated bile flow in control livers,

but did not affect GS-DNP secretion. TnorUDCA, but not norUDCA,

reversed TLCA-induced impairment of bile flow and, in part, GS-DNP

secretion. TnorUDCA and norUDCA did not significantly affect TLCA-

induced apoptosis. TnorUDCA was detected at millimolar levels in bile

of livers treated with TLCA + TnorUDCA for 20 min, but not at relevant

levels (< 0.1 mmol/l) in those treated with norUDCA.

Conclusions: Taurine conjugation is essential for the anticholestatic

action of norUDCA in cholestasis induced by TLCA in perfused rat liver.

_________________________________________

I think this is the most recent published information on 24-

norUrsodeoxycholic acid. As far as I am aware it has not yet been

tested for its efficacy in human PSC in clinical trials, and it is not

yet sold as a drug for treatment of human cholestatic diseases.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> http://www.ncbi.nlm.nih.gov/pubmed/16472600

>

> Hi,

>

> Does anybody know anything about this or if it is being sold ?

>

> Marna

>

[Guest guest]

Hi Marna;

As far as I know, the only group actively working on 24-

norUrsodeoxycholic acid is Dr. Trauner (in Austria) and his

collaborators (in different countries), mostly in animal models. I do

not know whether Dr. Trauner and colleagues have convinced a

pharmaceutical company to manufacture it yet. The person who first

synthesized it was Dr. Alan Hofmann (University of California, San

Diego) and he is one of Dr. Trauner's collaborators, and is presumably

the person providing this compound for their research?

Dr. Trauner and collaborators presented 3 papers at the " Falk Symposium

165, XX International Bile Acid Meeting, Bile Acid Biology and

Therapeutic Actions; June 13-14, 2008; Hotel Okura, Amsterdam, The

Netherlands " all dealing with their animal model work. The abstracts of

these papers are shown below:

_________________________________________

p. 54 of Abstract Booklet

Differential effects of ursodeoxycholic acid (UDCA) and sidechain-

shortened norUDCA in the treatment of fatty liver and atherosclerosis.

Fickert1, Tarek Moustafa1, Fuchsbichler2, Thierry Claudel1,

Emina Halilbasic1, Dagmar Kratky2, Kurt Zatloukal3, Helmut Denk3,

Trauner1

1Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Internal Medicine,

Medical University of Graz, Austria

2Institute of Molecular Biology and Biochemistry, Medical University of

Graz, Austria 3Institute for Pathology, Medical University of Graz,

Austria

Background: Beside their well established role in the regulation of

dietary lipid absorption and cholesterol homeostasis, bile acids may

also play a key role as endocrine signaling molecules that coordinate

hepatic lipid homeostasis through nuclear hormone receptors and thus

might represent a promising therapeutic treatment strategy for non-

alcoholic fatty liver disease (NAFLD) and arteriosclerosis.

However, ursodeoxycholic acid (UDCA), did not improve non-alcoholic

steatohepatitis (NASH) in humans (Lindor et al. Hepatology 2004) and

more effective therapies are needed. Moreover, UDCA has never has been

tested in models of atherosclerosis despite being known to reduce LDL-

cholesterol (LDL-C). We therefore aimed to explore the potential

therapeutic mechanisms of UDCA and its side chain-shortened homologue

norUDCA on NAFLD and arteriosclerosis in Western-diet fed ApoE-/- mice.

Methods: ApoE-/- mice were fed Western diet for 8 weeks (Co). Treatment

groups received either 0.5% UDCA or norUDCA in addition to Western diet

from week 4-8 (i.e. after development of hepatic steatosis and

athersosclersis). H&E and red oil staining, hepatic TG-levels,

expression of key genes in hepatic TG homeostasis, neutophil

infiltration and VCAM-1 expression, the degree of aortic (valve) plaque

formation, and serum lipid composition were compared.

Results: norUDCA significantly reduced hepatic triglyceride content,

induced FA oxidation (AOX mRNA expression), reduced TG synthesis (Lpin1

mRNA expression), neutrophil count, and VCAM expression. In addition,

norUDCA significantly reduced aortic plaques surface area and aortic

staining for macrophage marker F4/80. Interestingly, while UDCA

treatment significantly reduced total serum cholesterol and

triglyceride levels in ApoE-/- mice, norUDCA had no effect on both

parameters. However, FPLC-analysis clearly demonstrated an increase of

cholesterol and phospholipids in the HDL-fraction in norUDCA treated

animals when compared to Co. Moreover, norUDCA but not UDCA restored

Cyp7a1 expression in Western-diet fed animals.

Conclusions: norUDCA is superior to UDCA in the treatment of NAFLD and

arteriosclerosis in Western chow-fed ApoE-/- mice and these effects are

independent of total serum cholesterol and triglyceride levels. Due to

its multiple effects on lipoprotein composition, foam cell formation,

and hepatic lipid metabolism side-chain homologues of UDCA may

represent promising drugs to treat NAFLD and arteriosclerosis.

_________________________________________

p. 55 of Abstract Booklet

Side-chain-modification critically determines the physiologic and

therapeutic properties of 24-nor-ursodeoxycholic acid in the treatment

of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice and isolated

bile duct units.

Emina Halilbasic1, Fickert1, Romina Foirotto2 , Hanns Ulrich

Marschall3, Tarek Moustafa1, Fuchsbichler4, Judith Gumhold1,

Dagmar Silbert1, Cord Langner4, Uday Maitra5, Helmut Denk4 ,

Strazzabosco2, Trauner1

1Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Medicine, Medical

University Graz, Austria

2Section of Digestive Diseases, Department of Internal Medicine, School

of Medicine, Yale University, New Haven, USA

3Karolinska University Hospital Huddinge, Stockholm, Sweden

4Institute of Pathology, Medical University Graz, Austria

5Department of Organic Chemistry, Indian Institute of Science,

Bangalore, India

Background and aim: Nor-ursodeoxycholic acid (norUDCA) reverses

sclerosing cholangitis and biliary fibrosis in multidrug resistance

gene 2 knock-out (Mdr2-/-) mice. This may be critically related to the

relative conjugation resistance of norUDCA undergoing cholehepatic

shunting and inducing bicarbonate-rich hypercholeresis. To test this

hypothesis we compared the effects of norUDCA, its taurine conjugate

T-norUDCA, and further side chain shortened bis-norUDCA in Mdr2-/- mice

and isolated mouse bile duct units (IBDU).

Material and methods: 8 weeks-old Mdr2-/- mice were fed a standard chow

or a diet containing norUDCA, T-norUDCA or bis-norUDCA for 4 weeks.

Liver histology, serum liver enzymes, bile flow, markers of liver

fibrosis as well as mRNA expression of key detoxification and transport

systems were compared. Potential choleretic mechanisms in

cholangiocytes were addressed in IBDU in bicarbonate containing

and free medium.

Results: NorUDCA but not T-norUDCA, significantly reduced ALT/AP levels

and improved liver histology. In contrast, bis-norUDCA even

deteriorated the cholestatic phenotype. NorUDCA and bis-norUDCA

stimulated the expression of basolateral bile acid efflux pump Mrp4.

Induction of bile acid biotransformation enzymes (Cyp2b10 and Sult2a1)

was observed after norUDCA and bis-norUDCA treatment. Biliary

bicarbonate-output was 2-fold higher in norUDCA compared to T-norUDCA-

treated animals. NorUDCA stimulated bile secretion in IBDU more

potently than tauronorUDCA, effects which were partially bicarbonate-

dependent.

Summary and conclusion: NorUDCA is superior to its homologues in the

reduction of liver injury, ductular proliferation and periductal

fibrosis in Mdr2-/- mice, suggesting bicarbonate rich hypercholeresis

and cholehepatic shunting as its key mechanisms of action.

_________________________________________

p. 56 of Abstract Booklet

Role of side chain amidation for the anticholestatic action of norUDCA

in rat liver.

Silvia Maitz1,2, Ralf Wimmer1, Christian Rust1, Gerald U. Denk1, Pietro

Invernizzi2, Sacha Ferdinandusse3, J. Wanders3,

Fuchsbichler4, Fickert4, Trauner4, Alan F. Hofmann5,

Ulrich Beuers1,3

1Department of Medicine II, Klinikum Großhadern, University of Munich,

Germany

2Division of Internal Medicine and Liver Unit, San Paolo School of

Medicine,University of Milan, Italy

3Department of Gastroenterology & Hepatology, AMC, University of

Amsterdam, The Netherlands

4Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Medicine and Department

of Pathology, Medical University, Graz, Austria

5Division of Gastroenterology, Department of Medicine, University of

California, San Diego, CA, USA

Background and aim: The impact of taurine conjugation for the

anticholestatic effect of ursodeoxycholic acid (UDCA) and its taurine

conjugate (TUDCA) is unclear (Nature CP Gastr Hepat 2006; 3).

Norursodeoxycholic acid (norUDCA) exerts therapeutic effects superior

to UDCA in Mdr2/Abcb4 knockout mice (Mdr2-/-) that develop chronic

progressive sclerosing cholangitis (Gastroenterology 2006; 130:

465). In contrast to UDCA, norUDCA is poorly conjugated by rat and human

hepatocytes (Hepatology 2005; 42: 1319). Taurolithocholic acid (TLCA)-

induced cholestasis represents a well-established experimental model of

hepatocellular cholestasis. The aim of the present study was to compare

the effect of norUDCA and its taurine conjugate (TnorUDCA) on bile

formation and liver cell injury in TLCA-induced cholestasis of perfused

rat livers.

Methods: The effect of norUDCA and TnorUDCA (25 umol/l, each) on bile

flow and biliary secretion of the Mrp2 (Abcc2) substrate, 1,2-

dinitrophenyl-S-glutathione (GSDNP), was studied in presence or absence

of TLCA (10 umol/l) in isolated perfused rat livers (JBC 2003; 278:

17810). Bile acid administration was started after 45 min,

and 1-chloro-2,4-dinitrobenzene (CDNB, 30 umol/l), the precursor of GS-

DNP, was administered from min 65 to 75. Bile secretion was determined

gravimetrically, GSDNP secretion fluorometrically, biliary bile salt

composition by tandem mass spectrometry, and liver cell apoptosis by an

immunohistochemical approach (caspase 3, cytokeratin 18 staining).

Statistics: ANOVA with Tukey's post-hoc test.

Results: TnorUDCA and norUDCA stimulated bile flow in control livers,

but did not affect GS-DNP secretion. TnorUDCA, but not norUDCA,

reversed TLCA-induced impairment of bile flow and, in part, GS-DNP

secretion. TnorUDCA and norUDCA did not significantly affect TLCA-

induced apoptosis. TnorUDCA was detected at millimolar levels in bile

of livers treated with TLCA + TnorUDCA for 20 min, but not at relevant

levels (< 0.1 mmol/l) in those treated with norUDCA.

Conclusions: Taurine conjugation is essential for the anticholestatic

action of norUDCA in cholestasis induced by TLCA in perfused rat liver.

_________________________________________

I think this is the most recent published information on 24-

norUrsodeoxycholic acid. As far as I am aware it has not yet been

tested for its efficacy in human PSC in clinical trials, and it is not

yet sold as a drug for treatment of human cholestatic diseases.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> http://www.ncbi.nlm.nih.gov/pubmed/16472600

>

> Hi,

>

> Does anybody know anything about this or if it is being sold ?

>

> Marna

>