fibrate, Primary Sclerosing Cholangitis Literature

The mouse equivalent of the human MDR3 protein is Mdr2, encoded by the gene Abcb4. Mice deficient in Mdr2 (mdr2(-/-)) develop sclerosing cholangitis by a multistep process involving regurgitation of bile from leaky ducts into the portal tracts. This leads to induction of periductal inflammation, followed by activation of periductal fibrogenesis, finally causing obliterative cholangitis owing to atrophy and death of bile duct epithelial cells (Fickert et al., 2004). Fibrates induce Mdr2 expression in mice (Kok et al., 2003). Shoda et al. (2004) have suggested that the decreased function of ATP binding cassette protein B4 (ABCB4), which is rate-limiting for biliary phospholipid secretion, predisposes individuals to cholestasis and/or cholangitis. They show that bezafibrate may enhance the capacity of human hepatocytes to direct phospholipids into bile canaliculi via redistribution of ABCB4 to the canalicular membrane. They suggest that this provides a rationale for the use of bezafibrate to improve cholestasis and/or cholangitis due to impaired function of ABCB4 (Shoda et al., 2004).

Bezafibrate and fenofibrate are now being considered as experimental drugs (in combination with ursodeoxycholic acid) in PBC patients in Europe and the U.S.A. (Bergasa et al., 2004). Because fibrates modify the expression of key factors involved in bile-acid synthesis and biliary-lipid secretion in gallstone patients (Roglans et al., 2004), and it is well known that gallbladder disease (Said et al., 2008) and hypercholesterolemia (Jorgensen et al., 1995) are commonly associated with PSC, the potential effects of fibrates on these conditions associated with PSC might be worth evaluation.

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David and Judy Rhodes Last Update: 2/21/2010