Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid in the rhesus monkey

Fedorowski, Toni; Salen, Gerald; Zaki, F. G.; Shefer, Sarah; Mosbach, Erwin H.

doi:10.1016/0016-5085(78)90359-1

Cited by 59 publications

(8 citation statements)

References 17 publications

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“…Similarly, studies in several animal species have shown considerable functional and structural liver changes following the administration of cheno-or ursodeoxycholic acid (5-9), which could be attributed to an increase in biliary lithocholic acid concentration. In contrast, ursodeoxycholic acid administration was shown by Federowski et al (9) not to cause liver damage in Rhesus monkeys, and there was no significant increase in biliary lithocholic acid levels. However, contrary results have been presented by Sarva et al (10) who found that both cheno-and ursodeoxycholic acids increased biliary lithocholic acid and induced comparable abnormalities of liver function and structure.…”

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confidence: 68%

Early Morphologic and Enzymatic Changes in Livers of Rats Treated with Chenodeoxycholic and Ursodeoxycholic Acids

Shefer¹,

Zaki²,

Salen³

2007

Hepatology

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The effect of high doses of chenodeoxycholic and ursodeoxycholic acids on hepatic morphology and on cholesterol and bile acid metabolism was examined in the rat. After 2 weeks of either cheno or ursodeoxycholic acid feeding, the livers of the treated rats revealed marked proliferation of the smooth endoplasmic reticulum which appeared as an adaptation phenomenon of the microsomal enzyme system in response to bile acid intake. However, the livers of the chenodeoxycholic acidtreated rats showed early alteration that included mild triaditis, swelling of the bile canalicular microvilli, distended Golgi vesicles, whorling of the mitochondria, and presence of large vacuoles bound by single membranes. During cheno-or ursodeoxycholic acid treatment, the administered bile acid predominated in the bile and amounted to 79 or 67% of the biliary bile acids, respectively. At the same time, the concentration of the muricholic acids was also increased. Biliary cholic acid content dropped significantly, but no change in lithocholic acid concentration was observed. In addition, the activity of HMG-CoA reductase as well as that of cholesterol-7a-hydroxylase was reduced by either of the administered bile acids, while no change in hepatic cholesterol content was detected, and intestinal cholesterol absorption was not significantly different from that of controls.These results show that cheno-and ursodeoxycholic acids inhibited hepatic cholesterol and bile acid synthesis but did not increase either intestinal cholesterol absorption or hepatic microsomal cholesterol content. Since the amounts of biliary lithocholic acid were similar in the bile acidtreated animals, the morphologic abnormalities detected in the chenodeoxycholic acid-fed rats are probably due to an increased pool of chenodeoxycholic acid. However, lithocholic acid-induced liver injury cannot be excluded.Considerable information has been accumulated concerning the efficacy and safety of chenodeoxycholic acid and its 7P-hydroxy epimer ursodeoxycholic acid for the treatment of cholesterol cholelithiasis in man (1, 2). Despite wide-spread clinical use, the mechanism of action Received March 10, 1982; accepted October 7, 1982. This work was supported by Public Health Service Grants AM-26756, AM-18707, and HL-17818.The following systematic names are given to compounds referred to by trivial names: cholesterol, 5-cholesten-3P-ol; 7a-hydroxycholesterol, 5-cholestene-3/3,7au-diol; ,Chitosterol, 24P-ethyl-5-cholesten-3P-ol; cholic acid, 3a,7a, 12a-trihydroxy-5~-cholanoic acid; chenodeoxycholic acid, 3a,7a,dihydroxy-5P-cholanoic acid; ursodeoxycholic acid, 3a,7p-dihydroxy-5P-cholanoic acid lithocholic acid, 3a-hydroxy-5P-cholanoic acid; a-muricholic acid, 3a,6~,7a-trihydroxy-5~-cholanoic acid; p-muricholic acid, 3a,GP,7~-trihydroxy-5P-cholanoic acid isoursodeoxycholic acid, 3P,7~-dihydroxy-5P-cholanoic acid.Address reprint requests to:

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confidence: 68%

Early Morphologic and Enzymatic Changes in Livers of Rats Treated with Chenodeoxycholic and Ursodeoxycholic Acids

Shefer¹,

Zaki²,

Salen³

2007

Hepatology

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“…Serum enzymes of liver origin remained within normal limits and there were none of the histological features typical of CDCA toxicity: periportal inflamma tion, bile duct proliferation, or hepatic necrosis. Why UDCA fails to cause an increase in lithocholate is unknown; it has been suggested that UDCA suppresses intestinal bacterial activity or that the bacteria which dehy droxylate the 7 -hydroxy group are stereospecifi c (81).…”

Section: Ursodeoxycholic Acidmentioning

confidence: 99%

The Medical Treatment of Gallstones

Bouchier¹

1980

Annu. Rev. Med.

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“…A number of lines of evidence indicate that the accumulation of LCA in the enterohepatic circulation is responsible for the hepatotoxicity induced by the administration of CDCA or UDCA to experimental animals. First, the severity of hepatotoxicity induced by CDCA or UDCA feeding is roughly proportional to the enrichment of LCA in biliary bile acids in species such as the rabbit (2), rhesus monkey (3, 4) or baboon (5) that cannot detoxify LCA; second, CDCA and UDCA are not hepatotoxic in species such as the hamster (6, 71, prairie dog ( 8 ) or man (9, 10) that readily detoxify LCA by hydroxylation (reviewed in 11) or sulfation (12); third, in the CDCA-fed and UDCA-fed rhesus monkey, UDCA is toxic when LCA accumulated (3,4), but not when it does not accumulate (13). Finally, in species such as the squirrel monkey that do not form LCA in the colon because of its very short small intestine, CDCA is not toxic (14).…”

Section: :989-996)mentioning

confidence: 99%

“…The dehydroxylation is a multienzyme process that involves a 3-0xo-A~*~-diene intermediate (16) and is mediated by only a few species of anaerobic bacteria (15). The mechanism of absorption of bile acids from the colon is considered to be passive nonionic diffusion, that is, partition of the protonated hydrophobic molecule into lipid domains of the colonic enterocyte followed by transmembrane "flip-flop" (1 [7][8][9][10][11][12][13][14][15][16][17][18][19]. Such partitioning can only occur for unconjugated bile acids because conjugated bile acids are ionized to a much greater extent at colonic pH as a consequence of their lower pK, values (20).…”

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confidence: 99%

Prevention of ursodeoxycholate hepatotoxicity in the rabbit by conjugation withN-methyl amino acids

et al. 1990

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The effect of dietary administration of four different amino acid (N-acyl) conjugates of ursodeoxycholic acid on biliary bile acid composition, liver tests and hepatic morphology by light microscopy was examined in the rabbit. Each group of four to five rabbits received a chow diet supplemented with a single conjugate of ursodeoxycholic acid ursodeoxycholyl-glycine, ursodeoxycholyl-sarcosine, ursodeoxycholyl-taurine or ursodeoxycholyl-N-methyltaurine for 3 wks at a dose of 50 mg/kg/day; a control group received chow alone. After 3 wks of feeding, animals receiving ursodeoxycholyl-glycine or ursodeoxycholyl-taurine had hepatotoxicity associated with abnormal liver tests. Lithocholic acid made up 11% +/- 2.7% of biliary bile acids in the ursodeoxycholyl-glycine and 10% +/- 2.2% in the ursodeoxycholyl-taurine group. In contrast, animals receiving ursodeoxycholyl-sarcosine or ursodeoxycholyl-N-methyltaurine had neither hepatotoxicity nor abnormal liver tests and the proportion of lithocholic acid in biliary bile acids increased much less. Complementary studies showed that ursodeoxycholyl-sarcosine and ursodeoxycholyl-N-methyltaurine were not biotransformed during hepatic transport and were resistant to deconjugation and dehydroxylation in the rabbit. These experiments indicate that the N-methyl amino acid conjugates of ursodeoxycholic acid are nontoxic in the rabbit and resist deconjugation and dehydroxylation. Such resistance decreases formation of lithocholic acid in the colon, thus reducing its accumulation and consequent induction of hepatotoxicity.

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Comparative effects of ursodeoxycholic acid and chenodeoxycholic acid in the rhesus monkey

Cited by 59 publications

References 17 publications

Early Morphologic and Enzymatic Changes in Livers of Rats Treated with Chenodeoxycholic and Ursodeoxycholic Acids

Early Morphologic and Enzymatic Changes in Livers of Rats Treated with Chenodeoxycholic and Ursodeoxycholic Acids

The Medical Treatment of Gallstones

Prevention of ursodeoxycholate hepatotoxicity in the rabbit by conjugation withN-methyl amino acids

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