Alternative bile acid biosynthetic (acidic or sterol 27-hydroxylas) pathway

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Cholesterol is also oxidized by sterol 27-hydroxylase (CYP27A1) to 27-hydroxycholesterol and 3β-hydroxy-5-cholestenoic acid. These two compounds are converted to 7α,27- dihydroxycholesterol and 3β,7α-dihydroxy-5-cholestenoic acid, respectively, by oxysterol 7α- hydroxylase (CYP7B1). These oxidized metabolites are produced mainly in the peripheral tissues. Other enzymes involved in the alternative pathway are not well defined although many predicted intermediates of the alternative pathways have been identified in HepG2 cells and human hepatocytes. Since both CYP27A1 and CYP7B1 are expressed in various tissues and only the liver has the complete set of bile acid biosynthetic enzymes, these oxidized sterols must be transported to the liver in order to be converted to bile acids. The relative contribution of the classic and alternative pathways to overall bile acid synthesis is not clear. The classic pathway may be the main pathway that is highly regulated under physiological conditions, whereas the alternative pathway may contribute very little to overall bile acid synthesis under normal condition in humans, but may become the major bile acid biosynthetic pathway in patients with liver diseases. In humans, CA and CDCA are synthesized in about equal amounts. In the mouse and bear, CDCA is converted to muricholic acids (3α,6α/β,7β) and ursodeoxycholic acid (3α,7β) (UDCA), respectively. Muricholic acids and UDCA are soluble and non-cytotoxic. Human livers synthesize very small amount of UDCA. UDCA is a therapeutic drug approved for treating gallstone disease and primary biliary cirrhosis (Paumgartner 2003).

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