Ursodeoxycholic acid

In contrast to the effects of secondary bile acids like DCA, UDCA, which is found at a high concentration in bear bile but only in trace amounts in humans, has anti-neoplastic activity in vitro and in vivo. UDCA has significant chemopreventative activity in rodent models of sporadic and colitis-colorectal carcinogenesis induced by chemical carcinogens. 

UDCA has been used for treatment of patients with primary sclerosing 

The study authors pointed out the relatively short duration of this study may have limited the magnitude of any UDCA effect observed, particularly as the beneficial effect of UDCA on dysplasia incidence in one of the primary sclerosing cholangitis studies only became apparent after longer duration therapy.  

The mechanistic basis of the anti-neoplastic activity of UDCA and the explanation for the significant difference in bioactivity of UDCA compared with DCA despite marked similarity in chemical structure remain unresolved. UDCA administration in healthy volunteers and colorectal adenoma patients has been demonstrated to decrease the proportion of DCA in aqueous phase stool. Therefore, one possible mechanism of the chemopreventative activity of UDCA is reduction of mucosal secondary bile acid exposure. Consistent with this idea, UDCA administration has been demonstrated to reduce the incidence of K-ras mutations and decrease Cox-2 expression in AOM-induced tumors, which is the opposite of the reported effects of DCA in the same model. However, it is clear that exogenous administration of UDCA has direct anti-neoplastic activity on human CRC cells in vitro, either alone or in combination with DCA, including anti-proliferative and anti-apoptotic effects, as well as induction of cell senescence.  

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Multidimensional LC has also been used to determine ursodeoxycholic acid and its conjugates in serum (14). These compounds are used in the treatment of cholesterol gallstones, hepatitis and bilary cirrhosis. These authors employed a traditional (10 X 4 mm) pre-column and a micro-bore (35 X 2 mm) analytical column that were interfaced by using a six-port switching valve. 

Chenodeoxycholic acid Deoxycholic acid Lithocholic acid Ursodeoxycholic acid Muricholic acid... 

Lepercq P., Hermier D., David O., Michelin R., Gibard C., Beguet F., Relano, P., Cavuela C. and Juste C. (2005). Increasing ursodeoxycholic acid in the enterohepatic circulation of pigs through the administration of living bacteria . Br J Nutr, 93(4), 457 -69. 

Quaglia, M. G., Farina, A., Bossu, E., Dell Aquila, C., and Doldo, A. (1997). The indirect LTV detection in the analysis of ursodeoxycholic acid and related compounds by HPCE. /. Pharm. Biomed. Anal. 16, 281—285. 

J. D. Martinez, E. D. Stratagoules, J. M. LaRue, A. A. Powell, P. R. Gause, M. T. Craven, C. M. Payne, M. B. Powell, E. W. Gerner and D. L. Earnest, Different bile acids exhibit distinct biological effects the tumour promoter deoxycholic acid induces apoptosis and the chemopreventive agent ursodeoxycholic acid inhibits cell proliferation, Nutr. Cancer, 1998, 31(2), 111. 

The majority of micronuclei formed in this study were kinetochore negative, indicating a predominantly clastogenic effect of deoxycholic acid in these cells. Clastogenicity has previously been reported for organic fractions from human faeces and for ursodeoxycholic acid, utilising Chinese hamster ovary cells and human lymphocytes. 

Importantly, knowledge of intestinal bile acid transport and metabolism, coupled with increased understanding of the mechanistic basis of the pro-tumorigenic activity of bile acids against CRC cells in vitro, has recently led to development and testing of bile acid-based treatment and prevention strategies for sporadic and inflammatory bowel-disease-associated CRC. Existing evidence that manipulation of the luminal secondary bile acid pool and/or therapy with ursodeoxycholic acid (UDCA) may have promise for prevention of CRC will be assessed. 

Figure 5.2 Therapeutic interventions for decreasing colorectal mucosal bile acid exposure as a CRC chemoprevention strategy. 1) Lifestyle modifications including reduction in dietary animal fat and increased fibre intake may, at least partly, be explained by reduction in luminal primary (cholic acid [CA] and chenodeoxycholic acid [CDCA]) and secondary (deoxycholic acid [DCA] and lithocholic acid [LCA]) bile acids. 2) Reduction of secondary bile acids, which are believed to have pro-carcinogenic activity could be obtained by decreased bacterial conversion from primary bile acids. 3) Alternatively, bile acids could be sequestered by chemical binding agents, e.g. aluminium hydroxide (Al(OH)3) or probiotic bacteria. 4) Exogenous ursodeoxycholic acid (UDCA) can reduce the luminal proportion of secondary bile acids and also has direct anti-neoplastic activity on colonocytes in vitro.

R. K. Wall, D. Stoiber, L. Nguyen, J. Hart, M. D. Sitrin, T. Brasitus and M. Bissonnette, Ursodeoxycholic acid inhibits the initiation and postinitiation phases of azoxymethane-induced colonic tumour development. Cancer Epidemiol. Biomarkers Prev., 2002, 11, 1316. 

C. Loddenkemper, S. Keller, M.-L. Hanski, M. Cao, G. Jahreis, H. Stein, M. Zeitz and C. Hanski, Prevention of colitis-associated carcinogenesis in a mouse model by diet supplementation with ursodeoxycholic acid, Int. J. Cancer, 2006, 118, 2750. 

H. Kohno, R. Suzuki, Y. Yasui, S. Miyamoto, K. Wakabayashi and T. Tanaka, Ursodeoxycholic acid versus sulfasalazine in colitis-related colon carcinogenesis in mice, Clin. Cancer Res., 2007, 13, 2519. 

D. S. Pardi, E. V. Loftus, W. K. Kremers, J. Keach and K. Lindor, Ursodeoxycholic acid acts as a chemopreventive agent in patients with primary sclerosing cholangitis, Gastroenterology, 2001, 121, 900. 

J. M. Wolf, L. A. Rybicki and B. A. Lashner, The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis. Aliment. Pharmacol. Ther., 2005, 22, 783. 

L. Serfaty, A. De Leusse, O. Rosmorduc, B. Desaint, J.-F. Flejou, O. Chaouilleres, R. E. Poupon and R. Poupon, Ursodeoxycholic acid therapy and the risk of colorectal adenoma inpatients with primary biliary cirrhosis An observational study, Hepatology, 2003, 38, 203. 

L. M. Hess, M. F. Krutzsch, J. Guillen, H. H. Chow, J. Einspahr, A. K. Batta, G. Salen. M. E. Reid, D. L. Earnest and D. S. Alberts, Results of a phase I multiple-dose clinical study of ursodeoxycholic acid, Cancer Epidemiol. Biomarkers Prev., 2004, 13, 861. 

E. Im and J. D. Martinez, Ursodeoxycholic acid (UDCA) can inhibit deoxycholic acid (DCA)-induced apoptosis via modulation of EGFR/ERK signalling in human colon cancer cells, J. Nutr., 2004, 134, 483. 

S. Akare, S. Jean-Louis, W. Chen, D. J. Wood, A. A. Powell and J. D. Martinez, Ursodeoxycholic acid modulates histone acetylation and induces differentiation and senescence, Int. J. Cancer, 2006, 119, 2958. 

Graph 8.6 DCA, deoxycholic acid CDCA, chenodeoxycholic acid CA, cholic acid UDCA, ursodeoxycholic acid. Data taken from reference 24. 

The bile add ursodeoxycholic acid has shown some promise in slowing down the fibrotic process in cholestatic patients, especially those suffering from PBC and PSC [77,78]. Its mechanism of action, however, is stiU a matter of debate. 

Ursodeoxycholic acid = ursodiol Actigall, Destolit, Ursofalk... 

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