Ursodeoxycholic acid metabolism

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. 

Plasma and urine samples from atherosclerotic and control rats were comparatively analyzed by ultrafast liquid chromatography coupled with ion trap-time-of-flight (IT-TOF) MS (UFLC-IT/TOF-MS) (16). They identified 12 metabolites in rat plasma and 8 metabolites in rat urine as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcar-nitine, butyrylcamitine, propionylcamitine, and spermine in plasma and 3-0-methyl-dopa, ethyl /V2-acety I -1. -argininate, leucylproline, glucuronate, A(6)-(A-threonylcarbonyl)-adenosine, and methyl-hippuric acid in urine were decreased in atherosclerosis rats ursodeoxycholic acid, chenodeoxycholic acid, LPC (06 0), LPC (08 0), and LPC (08 1) in plasma and hippuric acid in urine were increased in atherosclerosis rats. The altered metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids, and amino acids. Lysophosphatidylcholine (LPC) plays an important role in inflammation and cell proliferation, which shows a relationship between LPC in the progress of atherosclerosis and other inflammatory diseases. 

Mazzella, G., Parini, P., Bazzoli, F., Villanova, N., Festi, D., Aldini, R., Roda, A., Cipolla, A., Polimeni, C., Tonelli, D., Roda, E Ursodeoxycholic acid administration on bile acid metabolism in patients with early stages of primary biliary cirrhosis. Dig. Dis. Sci. 1993 38 896-902... 

Rodriguez-Ortigosa, C.M., Cincu, R.N., Sanz, S., Ruiz, F., Quiroga, J., Prieto, J. Effect of ursodeoxycholic acid on methionine adeno-syltransferase activity and hepatic glutathione metabolism in rats. Gut... 

AvUa MA, Berasain C, Torres L, Martfn-Duce A, Corrales FJ, Yang H, Prieto J (2000) Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 33 907-914 Serviddio G, Pereda J, Pailardo FV, Carretero J, Borras C, Cutrin J, Vendemiale G, Poli G, Vina J, Sastre J (2004) Ursodeoxycholic acid protects against secondary biliary cirrhosis via up-regulation of y-glutamyl cysteine synthetase and prevention of mitochondrial oxidative stress. Hepatology (in press)... 

Recent investigations into the mechanism of action of these bile acids indicate that ursodeoxycholic acid has certain advantages over chenodeoxycholic acid in the context of the overall homeostasis of cholesterol metabolism (F6). In contrast to chenodeoxycholic acid, ursodeoxycholic acid does not suppress bile acid synthesis (H7), possibly because the a-orientation of the 7-hydroxyl group of chenodeoxycholic acid is required to inhibit cholesterol 7a-hydroxylase activity. Thus, cholesterol breakdown into bile acids is not reduced by ursodeoxycholic acid. Other favorable factors are that ursodeoxycholic acid has a reduced capacity to solubilize cholesterol into micellar solution compared to chenodeoxycholic acid and intestinal cholesterol absorption is decreased by this bile acid (F6, H7). However, in gallbladder bile the relative limitation of ursodeoxycholic acid for micellar solubilization of cholesterol is compensated for by an ability to transport... 

Other precursors of the muricholates via 6)8-hydroxylation include 5)8-cholanic acid [78], lithocholic acid [84-86], 7-oxolithocholic acid [95,96], and ursodeoxycholic acid (3a,7j6-dihydroxy-5/3-cholanic acid) [97], The rat metabolized 12a-hydroxy-5/S-cholanic acid to 6/S,12a-dihydroxy-5)S-cholanic acid [83] and a small amount of 6)3,7a,12a-trihydroxy-5 -cholanic acid [98]. 3a,6)8,12a-Trihydroxy-5)8-cholanic acid was isolated from urine of surgically jaundiced rats after administration of de-oxycholate [99]. A series of bile acids from rat bile of unconfirmed structures but containing the 6/3,7/3-diol will be reviewed in Section II1.3. 

Although the use of deuterium in drug metabolism involving the isotope cluster technique may be complicated by isotope effects, both cost and convenience have led most workers to rely on this isotope. Recent examples include reports on aminopyrine,pencycuron, phencyclidine, fentanyl, and diethylstilbestrol. In the case of steroids and their derivatives, ion cluster studies have been performed exclusively with deuterium-labeled substrates. Examples include investigations with [ HsJethynylestradiol,[ H2]4-hydroxyandrost-4-ene-3,17-dione, ]-ursodeoxycholic acid, " and [ Jbudesonide. ... 

Dilger K, Denk A, Heeg MH, Beuers U. No relevant effect of ursodeoxycholic acid on cytochrome P450 3A metabolism in primary biliary cirrhosis. Hepatology 2005 41 595-602. 

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