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Milkiewicz P, Roma MG, Elias E, et al. Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways. Gut. 2002;51(1):113-9doi: 10.1136/gut.51.1.113.
Milkiewicz, P., Roma, M. G., Elias, E., & Coleman, R. (2002). Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways. Gut, 51(1), 113-9. https://doi.org/10.1136/gut.51.1.113
Milkiewicz, P, et al. "Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways." Gut vol. 51,1 (2002): 113-9. doi: https://doi.org/10.1136/gut.51.1.113
Milkiewicz P, Roma MG, Elias E, Coleman R. Hepatoprotection with tauroursodeoxycholate and beta muricholate against taurolithocholate induced cholestasis: involvement of signal transduction pathways. Gut. 2002 Jul;51(1):113-9. doi: 10.1136/gut.51.1.113. PMID: 12077103; PMCID: PMC1773293.
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Gut. 2002 Jul;51(1):113-9. doi: 10.1136/gut.51.1.113.

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

Gut

P Milkiewicz, M G Roma, E Elias, R Coleman

Affiliations

  1. School of Biosciences, and Liver and Hepatobiliary Unit, University of Birmingham, Birmingham B17 2TT, UK.

PMID: 12077103 PMCID: PMC1773293 DOI: 10.1136/gut.51.1.113

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.

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