Effect of tauroursodeoxycholate and S-adenosyl-l-methionine on 17β-estradiol glucuronide-induced cholestasis

Milkiewicz, Piotr; Roma, Marcelo G.; Cárdenas, René; Mills, Charles O.; Elias, Elwyn; Coleman, Roger

doi:10.1016/s0168-8278(00)00066-0

Cited by 20 publications

(15 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Assuming that a similar interaction may occur between Mrp2 and EE 17␤-glucuronide, our finding that a reduced excretion of the cholestatic metabolite occurs in UDC-treated rats may explain the beneficial effect of this bile salt. These results are in accordance with prevention of estrogen-induced cholestasis by S-adenosylmethionine, which increases the formation of sulfate metabolites (Stramentinoli et al, 1981;Milkiewicz et al, 2001). These mechanisms of UDC and S-adenosylmethionine give additional support to the hypothesis that EE 17␤-glucuronide is the mediator of the cholestatic effect of EE.…”

Section: Discussionsupporting

confidence: 76%

“…The participation of other toxic metabolite of EE whose levels could be reduced by UDC cannot be ruled out in the light of our findings. Nevertheless, UDC prevention of EE cholestasis is not limited to decreased glucuronide formation since this bile salt has shown protective effects on acute cholestasis induced by estradiol 17␤-glucuronide in the rat (Kinbara et al, 1997;Milkiewicz et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Their beneficial effects on EE-induced cholestasis have been demonstrated in rats; e.g., UDC in-creases bile flow and bile salt output, leading to an improvement of the biliary secretory function impaired by EE (Bouchard et al, 1993;Jacquemin et al, 1993). TUDC also prevented the acute cholestasis induced by estradiol 17␤-glucuronide (Kinbara et al, 1997;Milkiewicz et al, 2001).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Pozzi¹,

Crocenzi²,

Pellegrino³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Ethinylestradiol (EE) administration (5 mg/kg, s.c., daily for 5 days) to rats leads to cholestasis, and its derivative EE 17␤-glucuronide is a likely mediator of this effect. Coadministration of ursodeoxycholate (UDC) was shown to prevent ethinylestradiol-induced cholestasis. The aim of this study was to evaluate the inhibitory effect of UDC on EE glucuronidation in vivo and in vitro as a potential mechanism to explain UDC protection. UDC treatment (25 mg/kg, i.p., daily for 5 days) decreased the biliary excretion of EE 17␤-glucuronide in bile after administration of a trace dose of [ 3 H]EE and reduced microsomal EE 17␤-glucuronidation activity by 20% and expression of UGT2B1, one of the enzymes involved in EE conjugation, by 30%. Glucuronidation kinetic studies were performed in vitro using normal microsomes and isolated hepatocytes in the presence of tauroursodeoxycholate (TUDC), the major endogenous derivative of UDC in the rat. Kinetic enzymatic studies in microsomes showed a noncompetitive inhibition of EE 17␤-glucuronidation by TUDC, which was unique for this bile salt since other endogenous bile salts such as taurocholate, taurochenodeoxycholate, or taurodeoxycholate did not affect the enzyme activity. Studies in isolated hepatocytes confirmed the inhibitory effect of TUDC on EE glucuronidation and indicated that TUDC can reach the enzyme active site in intact cells. In conclusion, both in vivo and in vitro experiments indicate that UDC decreased the metabolic pathways involved in EE glucuronidation, hence decreasing the formation of the cholestatic derivative EE 17␤-glucuronide.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Pozzi¹,

Crocenzi²,

Pellegrino³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Co-administration of SAMe and dehydroepiandrosterone (DHEA) abrogated the hepatoprotective effect of SAMe thus demonstrating competition between LCA and DHEA for DHEAST activity and providing direct evidence that sulphation of LCA was a key aspect of SAMe's hepatoprotective action. 9 Recent observations have demonstrated impaired functioning of MDR1 and SULT2A1 in the colon in patients with ulcerative colitis. Langmann et al (2004) showed an eleven-fold reduction in the expression of SULT2A1 in the colon of patients with ulcerative colitis.…”

Section: Defective Mechanisms and Disease Susceptibilitymentioning

confidence: 99%

Coordinated defence and the liver

Elias

Mills

2007

Clinical Medicine

Self Cite

View full text Add to dashboard Cite

-The liver is strategically placed to protect the body against a vast array of potentially harmful compounds. The steps involved include phase I metabolism which makes molecules more reactive and phase II reactions which generally enhance solubility in bile or urine. Recent discoveries have shown how regulation of these reactions is also closely allied to expression of membrane transporters which excrete the products of biotransformation into bile and prevent their reabsorptoion via the intestine. The coordinated activity of these various functions is orchestrated by orphan nuclear receptors which, in response to an encounter with a potential toxin, are able to induce expression of the genes involved in its biotransformation and excretion. Lithocholic acid (LCA) is routinely produced in our intestine by bacterial deconjugation of chenodeoxycholic acid a major bile acid in humans. In human liver the presence of LCA is sensed by the pregnane X receptor (PXR) which has the potential to switch on all the genes required for safe metabolism and elimination of LCA from the body. These include cytochrome P450 3A which hydroxylates LCA to more soluble forms and sulfotransferase (SULT2A1) which by sulphation of LCA makes it more readily soluble in bile and enhances its faecal excretion. Similarly, PXR exposure to LCA produces up-regulated expression of the membrane transporters MDR1 and MRP2 which excrete metabolites of LCA. Evidence is accumulating in support of the hypothesis that deficiencies in these defence mechanisms underlie susceptibility to primary sclerosing cholangitis and ulcerative colitis. KEY WORDS: cytochrome P450 3A, lithocholic acid, MDR1 and MRP2, orphan nuclear receptors, pregnane X receptor, sulphation, susceptibility to primary sclerosing cholangitis, ulcerative colitisThe liver metabolises and excretes a host of endogenous molecules and stands at the portal of entry for all kinds of ingested xenobiotics, whether food or drug. The fate of these compounds depends largely on the efficiency of their absorption from the gut and uptake and biotransformation by the liver. The mechanisms involved include metabolic transformation and active transport which usually work in combination to enhance elimination from the body whether in urine or faeces. In this the liver is closely allied with the intestine in maintaining the functionality of bile as a safe route for elimination of any potentially toxic compound that lacks sufficient solubility in water to permit its efficient excretion via the kidneys. The detergent properties of bile facilitate efficient excretion of compounds which are poorly soluble in water. Coordinated biliary defence mechanismsBile acids provide the required detergency and are essential for biliary cholesterol secretion and absorption of fat and fat soluble vitamins. The synthesis of bile acids by the liver is closely regulated to compensate for faecal loss, thus maintaining a consistent pool of bile acids in the entero-hepatic circulation which re-circulate from liver to intestine...

show abstract

“…The therapeutic bile acids ursodeoxycholate (UDCA) and its taurine conjugate tauroursodeoxycholate (TUDCA) have been effectively used for the treatment of cholestatic liver diseases including PBC (28,52) and PSC (17,55). The efficacy of UDCA or TUDCA is attributed to its cytoprotective effects (20,63), preventing apoptosis (11) and choleretic effects on hepatocytes (48) by increasing bile flow and biliary acid secretion (9) and hepatocellular vesicular exocytosis (12). TUDCA has been shown to be more effective than UDCA in the enrichment of biliary UDCA and more effectively absorbed by the intestine (31).…”

mentioning

confidence: 99%

Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca²⁺-, PKC-, and MAPK-dependent pathways

Alpini¹,

Kanno²,

Phinizy³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Tauroursodeoxychate (TUDCA) is used for the treatment of cholangiopathies including primary sclerosing cholangitis, which is considered the primary risk factor for cholangiocarcinoma. The effect of TUDCA on cholangiocarcinoma growth is unknown. We evaluated the role of TUDCA in the regulation of growth of the cholangiocarcinoma cell line Mz-ChA-1. TUDCA inhibited the growth of Mz-ChA-1 cells in concentration- and time-dependent manners. TUDCA inhibition of cholangiocarcinoma growth was blocked by BAPTA-AM, an intracellular Ca2+ concentration ([Ca2+]i) chelator, and H7, a PKC-α inhibitor. TUDCA increased [Ca2+]i and membrane translocation of the Ca2+-dependent PKC-α in Mz-ChA-1 cells. TUDCA inhibited the activity of MAPK, and this inhibitory effect of TUDCA was abrogated by BAPTA-AM and H7. TUDCA did not alter the activity of Raf-1 and B-Raf and the phosphorylation of MAPK p38 and JNK/stress-activated protein kinase. TUDCA inhibits Mz-ChA-1 growth through a signal-transduction pathway involving MAPK p42/44 and PKC-α but independent from Raf proteins and MAPK p38 and JNK/stress-activated protein kinases. TUDCA may be important for the treatment of cholangiocarcinoma.

show abstract

Effect of tauroursodeoxycholate and S-adenosyl-l-methionine on 17β-estradiol glucuronide-induced cholestasis

Cited by 20 publications

References 46 publications

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Coordinated defence and the liver

Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca²⁺-, PKC-, and MAPK-dependent pathways

Contact Info

Product

Resources

About

Effect of tauroursodeoxycholate and S-adenosyl-l-methionine on 17β-estradiol glucuronide-induced cholestasis

Cited by 20 publications

References 46 publications

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Ursodeoxycholate Reduces Ethinylestradiol Glucuronidation in the Rat: Role in Prevention of Estrogen-Induced Cholestasis

Coordinated defence and the liver

Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca2+-, PKC-, and MAPK-dependent pathways

Contact Info

Product

Resources

About

Tauroursodeoxycholate inhibits human cholangiocarcinoma growth via Ca²⁺-, PKC-, and MAPK-dependent pathways