Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways.

Abstract

BACKGROUND:

Tauroursodeoxycholate (TUDC) provides partial protection against taurolithocholate (TLC) induced cholestasis, possibly by inducing a signalling cascade activating protein kinase C (PKC). The potential protective effects of beta muricholic acid (beta-MC), another 7-beta-hydroxylated bile salt, have not previously been studied in TLC cholestasis.

AIMS:

To study the effect of beta-MC on TLC induced cholestasis and also to investigate further the effects of agents affecting intracellular signalling, notably DBcAMP (a cell permeable cAMP analogue) and several protein kinase inhibitors.

METHODS:

Functional studies were carried out analysing the proportion of hepatocyte couplets able to accumulate the fluorescent bile acid analogue cholyl-lysyl-fluorescein (CLF) into their sealed canalicular vacuole (cVA of CLF assay).

RESULTS:

It was found that both beta-MC and DBcAMP were as effective as TUDC in protecting against TLC induced cholestasis. The PKC inhibitors staurosporin and H7 but not the specific protein kinase A (PKA) inhibitor KT5720 abolished the protective effects of TUDC and beta-MC. BAPTA/AM, a chelator of intracellular Ca(2+), significantly decreased the protective effect of both bile salts, and that of DBcAMP. PKC and PKA inhibitors had no effect on protection with DBcAMP.

CONCLUSIONS:

Beta-MC was as effective as TUDC in protecting against TLC cholestasis. Mobilisation of Ca(2+) and activation of PKC, but not of PKA, are involved in the anticholestatic effect of the two 7-beta-hydroxylated bile salts. The hepatoprotective effects of DBcAMP involved Ca(2+) mobilisation, but not PKC or PKA activation.

• Authors: P Milkiewicz, M G Roma, E Elias, R Coleman
• Journal: Gut (Gut) Vol. 51 Issue 1 Pg. 113-9 (Jul 2002) ISSN: 0017-5749 [Print] England
• PMID: 12077103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbazoles
• Chelating Agents
• Cholagogues and Choleretics
• Cholic Acids
• Enzyme Inhibitors
• Indoles
• Pyrroles
• muricholic acid
• Taurochenodeoxycholic Acid
• Taurolithocholic Acid
• Egtazic Acid
• KT 5720
• ursodoxicoltaurine
• Bucladesine
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Cyclic AMP-Dependent Protein Kinases
• Protein Kinase C
• Staurosporine
• 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
• Calcium

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (pharmacology)
• Analysis of Variance
• Animals
• Bucladesine (metabolism)
• Calcium (metabolism)
• Carbazoles
• Chelating Agents (pharmacology)
• Cholagogues and Choleretics (therapeutic use)
• Cholestasis (chemically induced, metabolism, prevention & control)
• Cholic Acids (therapeutic use)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors)
• Egtazic Acid (analogs & derivatives, pharmacology)
• Enzyme Activation
• Enzyme Inhibitors (metabolism)
• Indoles (pharmacology)
• Liver (metabolism)
• Male
• Protein Kinase C (antagonists & inhibitors)
• Pyrroles (pharmacology)
• Rats
• Signal Transduction
• Staurosporine (pharmacology)
• Taurochenodeoxycholic Acid (therapeutic use)
• Taurolithocholic Acid