Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protective effect of ursodeoxycholate conjugates against bile salt hepatotoxicity was studied in chronic bile fistula rats. Taurochenodeoxycholate or taurodeoxycholate, infused intraduodenally at 24 or 16 mumols/100 g rat per hour, respectively, caused cholestasis and severe hepatocellular necrosis within 8 hours. In contrast, tauroursodeoxycholate or taurocholate at 48 mumols/100 g rat per hour were choleretic. Tauroursodeoxycholate was not hepatotoxic, whereas taurocholate produced moderate hepatocellular necrosis. Simultaneous infusion of tauroursodeoxycholate to rats receiving taurochenoxycholate or taurodeoxycholate preserved bile flow and ameliorated hepatic injury in a dose-dependent manner. Tauroursodeoxycholate protected equally by intravenous and intraduodenal routes. Intravenous glycoursodeoxycholate also was protective. The hydrophobicity index of infused bile salts correlated well with their toxicity. Concurrent administration of ursodeoxycholate conjugates did not reduce biliary recovery of intraduodenally infused [24-14C]-taurocholate. Biliary alkaline phosphatase secretion was stimulated by infusion of taurocholate, taurodeoxycholate, or taurochenodeoxycholate; simultaneous infusion of ursodeoxycholate conjugates failed to prevent this increase. We conclude that ursodeoxycholate counteracts hepatoxicity of more hydrophobic bile salts via a direct effect at the level of the liver.
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PMID:Conjugates of ursodeoxycholate protect against cholestasis and hepatocellular necrosis caused by more hydrophobic bile salts. In vivo studies in the rat. 198 22

We investigated bile flow and biliary excretion of bile acids in the Eisai hyperbilirubinemic rat, a Sprague-Dawley mutant rat with conjugated hyperbilirubinemia, using both in vivo and in vitro models. In vivo bile flow was lower in Eisai hyperbilirubinemic rats than in the control rats before and after taurocholate was infused. After taurocholate was infused, bile acid output was similar in the Eisai hyperbilirubinemic rats and control rats. In the isolated perfused rat liver, biliary excretion of bile acids was higher in the Eisai hyperbilirubinemic rats than in the control rats after a high-dose infusion of taurocholate (0.33 mumol/min/gm liver). Infusion of taurochenodeoxycholate (0.22 mumol/min/gm liver) did not produce cholestasis and did not reduce the biliary excretion of bile acids in the Eisai hyperbilirubinemic rats. Taurochenodeoxycholate significantly increased the phospholipid/bile acid molar ratio and slightly reduced bile acid-induced alkaline phosphatase output into bile. The release of lactate dehydrogenase from the perfused liver 30 min after the start of the taurochenodeoxycholate infusion was 10 times lower in the Eisai hyperbilirubinemic rats than in the control rats (2.0 +/- 0.8 vs. 28.7 +/- 6.8 mU/min/gm liver). When the isolated perfused rat liver was infused with a 1-min pulse of horseradish peroxidase (25 mg), we observed an early and late peak of biliary excretion of horseradish peroxidase. The Eisai hyperbilirubinemic rats showed a significant increase in the late peak.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The mutant Eisai hyperbilirubinemic rat is resistant to bile acid-induced cholestasis and cytotoxicity. 792 35

Hydrophobic bile salts induce either necrosis or apoptosis depending on the severity of the injury caused by them. Since bile salt-induced apoptosis is influenced by Ca2+- and protein kinase-signaling pathways, and both necrosis and apoptosis share common initiating mechanisms, we analyzed whether these signaling cascades also influence bile salt-induced necrosis in isolated rat hepatocytes. Taurochenodeoxycholate (TCDC, 0.25-1.50 mM, 2 h) reduced, in a dose-dependent manner, the percentage of viable hepatocytes, and increased the release of the cytosolic enzyme, lactate dehydrogenase (LDH) and alanine aminotransferase (ALAT), and that of the plasma membrane enzyme, alkaline phosphatase (AP). The PKC inhibitors, H7 (100 microM) and chelerythrine (2.5 microM), both prevented significantly TCDC-induced necrosis. On the contrary, the PKA activator, dibutyryl-cAMP, exacerbated TCDC-induced cell damage in a dose-dependent manner; this effect was more likely due to cAMP-mediated PKA activation, as the PKA inhibitor, KT5720 (1 microM), counteracted this effect. Instead, the intracellular Ca2+ chelator, BAPTA/AM (20 microM), was without effect. TCDC (1 mM) increased lipid peroxidation from 0.7 +/- 0.2 to 7.5 +/- 0.9 nmol of malondialdehyde per mg of protein, p < 0.001; the addition of the free radical scavenger, diphenyl-p-phenylendiamine, completely blocked this increase and prevented significantly TCDC-induced necrosis. PKC inhibition induced only a slight attenuation of TCDC-induced lipid peroxidation. Possible mechanisms accounting for the modulatory effect of signal transduction pathways on TCDC-induced necrosis, including signaling influence on TCDC transport events and TCDC-induced oxidative stress, are discussed.
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PMID:Signaling modulation of bile salt-induced necrosis in isolated rat hepatocytes. 1549 97