S-adenosyl-l-methionine protection against α-naphthyl- isothiocyanate-induced cholestasis in the rat

Padovaa, Carlo Di; Padova, Franco Di; Tritapepe, R; Stramentinoli, G.

doi:10.1016/0378-4274(85)90033-5

Cited by 24 publications

(10 citation statements)

References 16 publications

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“…Serum bilirubin levels were elevated nearly 50-fold following ANIT treatment, and bile acids were increased 25-fold. Table 1 Primer-probe sets and gene abbreviations These data demonstrate that ANIT exposure induced profound cholestasis and hepatocellular damage in the rats and are in line with earlier publications (26,27). GW4064 treatment resulted in substantial, statistically significant reductions in serum activities of ALT, AST, LDH, and ALP in the ANIT-treated rats ( Figure 1).…”

Section: Fxr Activation Is Hepatoprotective In Intrahepatic Cholestasissupporting

confidence: 72%

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

Liu¹,

Binz²,

Numerick³

et al. 2003

J. Clin. Invest.

345

209

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Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and α-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.This article was publised online in advance of the print addition. The date of publication is available from the JCI website, http://www.jci.org.

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Section: Fxr Activation Is Hepatoprotective In Intrahepatic Cholestasissupporting

confidence: 72%

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

Liu¹,

Binz²,

Numerick³

et al. 2003

J. Clin. Invest.

345

209

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“…This is in accordance with previous studies in which the administration of this vehicle (Farthing & Clark 1981) or SAMe alone (Di Padova et al 1985;Stra-mentinoli et al 1977) did not lead to observable effects on biliary secretion in the rat. This is in accordance with previous studies in which the administration of this vehicle (Farthing & Clark 1981) or SAMe alone (Di Padova et al 1985;Stra-mentinoli et al 1977) did not lead to observable effects on biliary secretion in the rat.…”

Section: Resultssupporting

confidence: 93%

Cyclosporin A-Induced Cholestasis in the Rat

et al. 1992

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Cyc1osporin A, a powerful immunosuppressor drug, induces nephrotoxicity and hepatotoxicity. The purpose of this study was to evaluate the ability of S-adenosyl-L-methionine (SAMe) to antagonise the cyc1osporin A-induced hepatotoxicity in rats treated with cyc1osporin A plus SAMe. Cyc1osporin A treatment for I or 2 weeks increases plasma bilirubin, alters some plasma biochemical indicators of hepatic and renal function, causes cholestasis and reduces the biliary concentration and secretion of bile acid and other bile components. SAMe pretreatment and simultaneous treatment with SAMe plus cyc1osporin A suppresses bilirubin increases in plasma, attenuates cholestasis and totally antagonises the adverse effects of cyc1osporin A on bile acid secretion. Although cyc1osporin A-induced hepatotoxicity in the rat is a multifactorial phenomenon, we suggest that the hepatoprotective effects of SAMe against cyc1osporin A could be related to its regulatory function of membrane lipid composition and fluidity, either alone or combined with stimulation of the hepatic synthesis of thiol compounds.

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“…In this respect, it is interesting to note that the administration of pharmacological doses of S-adenosyl-L-methionine could normalize phospholipid N-methylation in rat hepatocytes treated with transmethylation inhibitors (25). Furthermore, S-adenosyl-L-methionine administration has been shown to have a beneficial effect in several experimental models of hepatic intoxication (26)(27)(28)(29) and in several elinical trials (30, 31). It would be interesting to know if long-term treatment of cirrhotic patients with high doses of S-adenosyl-L-methionine would influence the course of the disease.…”

Section: Discussionmentioning

confidence: 99%

S -adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis

et al. 1988

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We have measured the activity S-adenosyl-L-methionine synthetase in liver biopsies from a group of controls (n = 17) and in 26 cirrhotics (12 alcoholic and 14 posthepatic). The activity of this enzyme was markedly reduced in the group of cirrhotics (285 +/- 32 pmoles per min per mg protein) when compared with that observed in controls (505 +/- 37 pmoles per min per mg protein). No differences in S-adenosyl-L-methionine synthetase was observed between both groups of cirrhotics. Similarly, a marked reduction in the activity phospholipid methyltransferase was also observed in liver biopsies from the same group of cirrhotics (105 +/- 12 pmoles per min per mg protein) when compared with the control subjects (241 +/- 13 pmoles per min per mg protein). Again, no difference in the activity of this enzyme was observed between both groups of cirrhotics. These results indicated a marked deficiency in the metabolism of S-adenosyl-L-methionine in cirrhosis.

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S-adenosyl-l-methionine protection against α-naphthyl- isothiocyanate-induced cholestasis in the rat

Cited by 24 publications

References 16 publications

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

Cyclosporin A-Induced Cholestasis in the Rat

S -adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis

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