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An abstract in a supplement of the Journal of Hepatology:

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J. Hepatol. 46: S51 (2007)

116. TAURINE-CONJUGATION CRITICALLY DETERMINES THE THERAPEUTIC

EFFECTIVENESS OF 24-NOR-URSODEOXYCHOLIC ACID (NORUDCA) IN THE

TREATMENT OF SCLEROSING CHOLANGITIS IN MDR2 (ABCB4) KNOCKOUT MICE

E. Halilbasic 1 , P. Fickert 1, A. Fuchbichler 2 , C. Langner 2, J.

Gumhold 1, D. Silbert 1, U. Maitra 3, K. Zatloukal 2, H. Denk 2, M.

Trauner 1.

1 Department of lnternal Medicine, Medical University of Gruz, Graz;

2 lnstitut of Pathology, Medical University of Graz, Graz, Austria;

3 Department of Organic Chemistry, Indian Institut of Science,

Bangalore, India

E-mail: emina.halilbasic@...

Background and Aims: We recently demonstrated that norUDCA reverses

sclerosing cholangitis and biliary fibrosis in Mdr2-/- mice (Fickert

et al., Gastroenterology, 2006) and hypothesized that its therapeutic

efficacy may be critically related to its relative resistance against

taurine- and glycine-conjugation resulting in cholehepatic shunting

and bicarbonate-rich hypercholeresis (Hofmann et al., Hepatology,

2005). Therefore we aimed to compare the therapeutic mechanisms and

effects of norUDCA and its taurine conjugate (TnorUDCA) in the Mdr2-/-

model for sclerosing cholangitis.

Methods: Adult Mdr2-/- mice were fed a diet containing norUDCA or

TnorUDCA (0.5% wt/wt) for 4 weeks, controls received standard chow.

Liver histopathology was assessed semi-quantitatively using a

modified scoring system (Nieuwkierk et al., Gastroenterology, 1996)

considering mitotic activity, apoptosis, portal inflammation,

ductular proliferation and fibrosis. Effects on bile flow and

composition, serum liver enzymes, markers of hepatic fibrosis (alpha-

smooth muscle actin, aSMA) and ductular proliferation (cytokeratin

19, CK19) as well as mRNA expression of key detoxification enzymes

and transport systems were compared.

Results: norUDCA resulted in stronger reductions of serum ALT and AP

levels, hepatic aSMA expression and improvement of liver histology

than TnorUDCA. Moreover, norUDCA reduced CK19 protein levels (30% of

untreated controls, p <0.05), while TnorUDCA only tended to reduce

ductular proliferation. Likewise, norUDCA stimulated the expression

of alternative basolateral bile acid efflux systems such as Mrp4 (3-

fold, p <0.05), while induction by TnorUDCA was less pronounced (1.5-

fold, p <0.05). A significant induction of mRNA expression of

biotransformation enzymes (Cyp2bl0, 10-fold, p <0.05; Sult2a1, 31-

fold versus TnorUDCA) was observed only with norUDCA. Both, norUDCA

and TnorUDCA stimulated bile flow as well as biliary output of

bicarbontate, bile acids and glutathione compared with untreated

controls. However, biliary bicarbonate-output was 2-fold higher in

norUDCA than TnorUDCA treated animals (p <0.05).

Conclusion: norUDCA is superior to TnorUDCA in the reduction of liver

injury, periductal fibrosis and ductular proliferation in Mdr2-/-

mice suggesting that its relative resistance to taurine-conjugation

critically determines the therapeutic efficacy.

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Other relevant articles that we discussed last year:

Fickert P, Wagner M, Marschall HU, Fuchsbichler A, Zollner G,

Tsybrovskyy O, Zatloukal K, Liu J, Waalkes MP, Cover C, Denk H,

Hofmann AF, Jaeschke H, Trauner M 2006 24-norUrsodeoxycholic acid is

superior to ursodeoxycholic acid in the treatment of sclerosing

cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 130: 465-

481.

Hofmann AF, Zakko SF, Lira M, Clerici C, Hagey LR, Lambert KK,

Steinbach JH, Schteingart CD, Olinga P, Groothuis GM 2005 Novel

biotransformation and physiological properties of norursodeoxycholic

acid in humans. Hepatology 42: 1391-1398.

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Dave

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