skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity

Abstract

Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (< 5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered,more » they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1 > TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.« less

Authors:
;  [1];  [2]; ;  [1];  [3]
  1. Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd. University of Salamanca, Salamanca (Spain)
  2. Facultad de Ciencias, Departamento de Quimica Fisica, Campus of Lugo, University of Santiago (Spain)
  3. Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd. University of Salamanca, Salamanca (Spain), E-mail: jjgmarin@usal.es
Publication Date:
OSTI Identifier:
21272623
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 239; Journal Issue: 1; Other Information: DOI: 10.1016/j.taap.2009.04.017; PII: S0041-008X(09)00170-7; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BILE; BILE ACIDS; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; INJURIES; KIDNEYS; LIVER; MUSHROOMS; NECROSIS; POLYMERIZATION; POLYPEPTIDES; RATS; SECRETION; TOXICITY

Citation Formats

Herraez, Elisa, Macias, Rocio I.R., Vazquez-Tato, Jose, Hierro, Carlos, Monte, Maria J., and Marin, Jose J.G. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity. United States: N. p., 2009. Web. doi:10.1016/j.taap.2009.04.017.
Herraez, Elisa, Macias, Rocio I.R., Vazquez-Tato, Jose, Hierro, Carlos, Monte, Maria J., & Marin, Jose J.G. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity. United States. doi:10.1016/j.taap.2009.04.017.
Herraez, Elisa, Macias, Rocio I.R., Vazquez-Tato, Jose, Hierro, Carlos, Monte, Maria J., and Marin, Jose J.G. Sat . "Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity". United States. doi:10.1016/j.taap.2009.04.017.
@article{osti_21272623,
title = {Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity},
author = {Herraez, Elisa and Macias, Rocio I.R. and Vazquez-Tato, Jose and Hierro, Carlos and Monte, Maria J. and Marin, Jose J.G.},
abstractNote = {Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (< 5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous bile acids. When highly choleretic bile acids, - ursodeoxycholic (UDCA) and dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing phalloidin-induced cholestasis. Biliary phalloidin elimination was low but it was increased by BALU-1 > TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.},
doi = {10.1016/j.taap.2009.04.017},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 239,
place = {United States},
year = {Sat Aug 15 00:00:00 EDT 2009},
month = {Sat Aug 15 00:00:00 EDT 2009}
}
  • Hepatocyte uptake of phalloidin is carried out mainly by OATP1B1. We have used this compound as a prototypic substrate and assayed the ability to inhibit OATP-mediated phalloidin transport of four bile acid derivatives (BALU-1, BALU-2, BALU-3 and BALU-4) that showed positive results in preliminary screening. Using Xenopus laevis oocytes for heterologous expression of transporters, BALUs were found to inhibit taurocholic acid (TCA) transport by OATP1B1 (but not OATP1B3) as well as by rat Oatp1a1, Oatp1a4 and Oatp1b2. The study of their ability to inhibit sodium-dependent bile acid transporters revealed that the four BALUs induced an inhibition of rat Asbt-mediated TCAmore » transport, which was similar to TCA-induced self-inhibition. Regarding human NTCP and rat Ntcp, BALU-1 differs from the other three BALUS in its lack of effect on TCA transport by these proteins. Using HPLC-MS/MS and CHO cells stably expressing OATP1B1 the ability of BALU-1 to inhibit the uptake of phalloidin itself by this transporter was confirmed. Kinetic analysis using X. laevis oocytes revealed that BALU-1-induced inhibition of OATP1B1 was mainly due to a competitive mechanism (Ki = 8 {mu}M). In conclusion, BALU-1 may be useful as a pharmacological tool to inhibit the uptake of compounds mainly taken up by OATP1B1 presumably without impairing bile acid uptake by the major carrier accounting for this process, i.e., NTCP.« less
  • Isolated neonatal cardiac myocytes have been utilized as a model for the study of cardiac arrhythmogenic factors. The myocytes respond to the toxic effects of a potent cardiac glycoside, ouabain at 0.1 mM, by an increase in their spontaneous beating rate and a reduction in amplitude of contractions resulting within minutes in a lethal state of contracture. Incubating the isolated myocytes for 3{endash}5 days in culture medium enriched with 5 {mu}M arachidonic acid had no effect on the development of lethal contracture after subsequent exposure to 0.1 mM ouabain. By contrast, incubating the myocytes for 3{endash}5 days with 5 {mu}Mmore » eicosapentaenoic acid completely prevented the toxic effects of ouabain at 0.1 mM. No differences in bumetanide-inhibitable {sup 86}Rb flux were observed between the three preparations. However, measurements with fura-2 of cytosolic free calcium levels indicated that control and arachidonic acid-enriched myocytes developed toxic cytosolic calcium concentrations of 845 {plus minus} 29 and 757 {plus minus} 64 nM, respectively, on exposure to 0.1 mM ouabain, whereas in eicosapentaenoic acid-enriched myocytes, physiologic calcium levels were preserved. Incubating the myocytes with eicosapentaenoic acid for 3{endash}5 days resulted in a small reduction of arachidonic acid and a small but significant increase of eicosapentaenoic acid in membrane phospolipids of the myocytes.« less
  • The relative rate of radical inactivation by p-aminobenzoic acid, pyridoxine, 2-mercaptoethylguanidine, Ndimethylcysteamine, N-(2-mercaptoethyl)- piperidine, and N-dibutylcysteamine have been studied in a two-solute system with pyridoxal-5-phosphate as indicator of radiation damage. The protection indices of these compounds were found to be 3.1 (extrapolated to zero concentration of the indicator), 1.3, 1.2, 0.8, 0.6, and 0.5, respectively. When the concentration of the indicator was increased from 9 x l0/sup -5/ M to 2.l x 10/ sup -4/ M, the protection index of p-aminobenzoic acid decreased from 2.3 to 1.4, thus giving evidence of energy transfer from p-aminobenzoic acid to the indicator. Themore » lack of correlation between radical scavenging effect in vitro and the ability of the compounds to exert radioprotection in vivo, suggests that this effect in vivo is largely dependent on biochemical factors. (auth)« less
  • After exposure to 5,000 r x irradiation, bile duct cells appear normal on microscopical examination. Evidence of irradiation damage is found if duct proliferation is stimulated by ligation of the common bile duct. (auth)
  • To investigate the effect of pulmonary oxygen toxicity and nitric acid-induced lung damage on absorption of drugs from the lung, rats were either exposed continuously to approximately 100% oxygen or given an intratrachael injection of 1% nitric acid solution (0.15 ml), and rates of drug absorption from damaged and control lungs were compared after various times. To measure pulmonary absorption rates, 0.1 ml of drug solution (0.1-10 mM) was administered through a tight-fitting trachael cannula to anesthetized animals, and, after various times, lungs were assayed for unabsorbed drug. Drugs investigated were procaine amide ethobromide, p-aminohippuric acid, procaine amide and mannitol-/supmore » 14/C. Rates of drug absorption were increased 1.1-1.2 fold after 48-54 hrs of continuous oxygen exposure and 1.3-1.6 fold at 1-4 days after nitric acid treatment. The results suggest that both types of lung damage increase the porosity of the absorbing membrane, and that nitric acid damage also alters the integrity of lipoid regions of the membrane.« less