Latest on nor-ursodeoxycholic acid

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Hepatology [in Press] (2009]

Side chain structure determines unique physiologic and therapeutic properties of

norursodeoxycholic acid in Mdr2-/- mice.

Halilbasic E, Fiorotto R, Fickert P, Marschall HU, Moustafa T, Spirli C,

Fuchsbichler A, Gumhold J, Silbert D, Zatloukal K, Langner C, Maitra U, Denk H,

Hofmann AF, Strazzabosco M, Trauner M

Keywords

bile acids • bile secretion • biliary fibrosis • ursodeoxycholic acid • taurine

amidation

Abstract

24-norursodeoxycholic acid (norUDCA), a side chain-modified UDCA derivative, has

dramatic therapeutic effects in experimental cholestasis and may be a promising

agent for the treatment of cholestatic liver diseases. We aimed to better

understand the physiologic and therapeutic properties of norUDCA and to test if

they are related to its side chain length and/or relative resistance to

amidation. For this purpose Mdr2-/- mice, a model for sclerosing cholangitis,

received either standard diet or norUDCA, tauro-norUDCA (taurine-conjugated

norUDCA) or dinorUDCA (a norUDCA homologue with a shorter side chain) enriched

diet. Bile composition, serum biochemistry, liver histology, fibrosis, and

expression of key detoxification and transport systems were investigated. Direct

choleretic effects were addressed in isolated bile duct units (IBDUs). The role

of cystic fibrosis transmembrane conductance regulator (Cftr) for

norUDCA-induced choleresis was explored in Cftr-/- mice. NorUDCA had

pharmacologic features that were not shared by its derivatives, including the

increase in hepatic and serum bile acid levels and a strong stimulation of

biliary HCO3--output. NorUDCA directly stimulated fluid secretion in IBDUs in a

HCO3--dependent fashion to a higher extent than the other bile acids. Notably,

the norUDCA significantly stimulated HCO3--output also in Cftr-/- mice. In

Mdr2-/- mice, cholangitis and fibrosis strongly improved with norUDCA, remained

unchanged with tauro-norUDCA and even worsened with dinorUDCA. Expression of

Mrp4, Cyp2b10 and Sult2a1 was increased by norUDCA and dinorUDCA, but unaffected

by tauro-norUDCA. Conclusion: The relative resistance of norUDCA to amidation

may explain its unique physiologic and pharmacologic properties. These include

the ability to undergo cholehepatic shunting and to directly stimulate

cholangiocyte secretion, both resulting in a HCO3--rich hypercholeresis that

protects the liver from cholestatic injury.

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Background - some of you may recall that the side-chain shortened version of

ursodeoxycholic acid (UDCA) - called norursodeoxycholic acid (norUDCA) - has

shown promise in blocking (and reversing) liver fibrosis in a mouse model of

sclerosing cholangitis, resembling human PSC. The earlier studies in this mouse

model, lacking a gene that encodes an important bile transport protein, Mdr2,

that transports phospholipids into the bile, showed that norUDCA was superior to

regular UDCA. Earlier it was shown that the norUDCA stimulated bicarbonate

(HCO3-) secretion into the bile (HCO3--rich hypercholeresis). In this study they

confirmed that this HCO3--rich hypercholeresis occurred, not only in the Mdr2

knockout mouse, but also in Cftr knock out mouse. This seems kind of surprising

since Cftr (the cystic fibrosis gene) is thought to be responsible for

bicarbonate secretion into bile! The other major finding in this study is that

modification of the norUDCA into its taurine conjugate, or by further

shortening the molecule (dinorUDCA) did not improve its function. Thus, norUDCA

would seem to be the best candidate to go forward to human trials.

Dave

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