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Cholemic transgenic mice: a novel animal model to investigate the effects of bile acids.

Abstract：

INTRODUCTION:Laboratory investigations into cholestatic liver disease and the effects of cholemia on organ function are long-standing subjects of scientific enquiry. A widely-used strategy to investigate these topics relies on animal-based research using experimental animal models. Targeted inactivation of the spgp gene, the gene responsible for expressing the bile salt export pump (BSEP) in the hepatocyte canalicular membrane impairs the canalicular secretion of bile salts resulting in systemic cholemia. The results of in vitro experiments have established bile acids as pro-oxidants and the collection of unambiguous in vivo data on the pro-oxidant activity of bile acids in the existing models of cholemia cannot be done. Therefore, we decided to use these genetically modified mice to determine whether this model of cholemia has evidence of extrahepatic or systemic oxidative stress, one of the features of cholestatic liver disease. METHODS:The extent of lipid peroxidation in livers, kidneys, hearts and brains harvested from cholemic homozygous (spgp -/-) mice using the thiobarbituric acid reactive substances (TBARS) assay. The data were compared to equivalent data collected from heterozygous (spgp +/-) and control mice. RESULTS:We found (1) substantial increases in malondialdehyde (MDA) levels in the brains and hearts; (2) a moderate increase in MDA levels in the kidneys; and (3) no change in MDA levels in the livers of the homozygous cholemic mice compared to the control and heterozygous mice. DISCUSSION:The transgenic mouse model of cholemia has an intact enterohepatic circulation and is uncomplicated by the adverse consequences of hepatotoxins or biliary surgery. Hepatocellular injury, as well as plasma and tissue accumulation of bilirubin and other liver-derived compounds are also negligible. Although this preliminary study could not establish a causal relationship between cholemia and oxidative stress, we believe this model is worthy of further investigation to study the impact of short-term and long-term cholemia on diverse physiological and biochemical functions such as trying to establish a causal role for bile acids in the development of oxidative stress in cholestatic liver disease.

journal_name

J Pharmacol Toxicol Methods

journal_title

Journal of pharmacological and toxicological methods

authors

Ljubuncic P,Yousef I,Bomzon A

doi

10.1016/j.vascn.2004.06.002

keywords:

subject

Has Abstract

pub_date

2004-11-01 00:00:00

pages

231-5

issue

eissn

1056-8719

issn

1873-488X

pii

S1056-8719(04)00057-7

journal_volume

pub_type

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Cholemic transgenic mice: a novel animal model to investigate the effects of bile acids.